Inhibitors of hcv ns5a

ABSTRACT

Provided herein are compounds, pharmaceutical compositions, and combination therapies for inhibition of hepatitis C.

STATEMENT OF RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/132,605, filed Jun. 2, 2011, which in turn is an application filedunder 35 U.S.C. §371 as the U.S. national phase of InternationalApplication PCT/US2009/066459, filed Dec. 2, 2009, which designated theU.S. and claims the benefit of U.S. provisional applications 61/119,723filed Dec. 3, 2008; 61/173,590 and 61/214,881 filed Apr. 28, 2009; and61/182,958 and 61/182,952 filed Jun. 1, 2009, the entire disclosure ofall of which, including any drawings, is hereby incorporated byreference herein.

FIELD OF THE INVENTION

The invention relates to compounds useful for inhibiting hepatitis Cvirus (“HCV”) replication, particularly functions of the non-structural5A (“NS5A”) protein of HCV.

BACKGROUND OF THE INVENTION

HCV is a single-stranded RNA virus that is a member of the Flaviviridaefamily. The virus shows extensive genetic heterogeneity as there arecurrently seven identified genotypes and more than 50 identifiedsubtypes. In HCV infected cells, viral RNA is translated into apolyprotein that is cleaved into ten individual proteins. At the aminoterminus are structural proteins: the core (C) protein and the envelopeglycoproteins, E1 and E2. p7, an integral membrane protein, follows E1and E2. Additionally, there are six non-structural proteins, NS2, NS3,NS4A, NS4B, NS5A and NS5B, which play a functional role in the HCVlifecycle. (see, for example, Lindenbach, B. D. and C. M. Rice, Nature.436:933-938, 2005).

Infection by HCV is a serious health issue. It is estimated that 170million people worldwide are chronically infected with HCV. HCVinfection can lead to chronic hepatitis, cirrhosis, liver failure andhepatocellular carcinoma. Chronic HCV infection is thus a majorworldwide cause of liver-related premature mortality.

The present standard of care treatment regimen for HCV infectioninvolves interferon-alpha, alone, or in combination with ribavirin. Thetreatment is cumbersome and sometimes has debilitating and severe sideeffects and many patients do not durably respond to treatment. New andeffective methods of treating HCV infection are urgently needed.

SUMMARY OF THE INVENTION

Essential features of the NS5A protein of HCV make it an ideal targetfor inhibitors. The present disclosure describes a class of compoundstargeting the NS5A protein and methods of their use to treat HCVinfection in humans.

In a first aspect, compounds of formula I are provided:

wherein:

-   -   A′ is selected from the group consisting of single bond,        —(CR₂)_(n)—C(O)—(CR₂)_(p)—, —(CR₂)_(n)—O—(CR₂)_(p)—,        —(CR₂)_(n)—N(R^(N))—(CR₂)_(p)—,        —(CR₂)_(n)—S(O)_(k)—N(R^(N))—(CR₂)_(p)—,        (CR₂)_(n)—C(O)—N(R^(N))—(CR₂)_(p)—,        —(CR₂)_(n)—N(R^(N))—C(O)—N(R^(N))—(CR₂)_(p)—,        —(CR₂)_(n)—C(O)—O—(CR₂)_(p)—,        —(CR₂)_(n)—N(R^(N))—S(O)_(k)—N(R^(N))—(CR₂)_(p)— and        —(CR₂)_(n)—N(R^(N))— C(O)—O—(CR₂)_(p) and a heteroaryl group        selected from the group consisting of

-   -    wherein        -   X¹ is CH₂, NH, O or S,        -   Y¹, Y² and Z¹ are each independently CH or N,        -   X² is NH, O or S,        -   V is —CH₂—CH₂—, —CH═CH—, —N═CH—,            —(CH₂)_(a)—N(R^(N))—(CH₂)_(b)— or —(CH₂)_(a)—O—(CH₂)_(b)—,            wherein a and b are independently 0, 1, 2, or 3 with the            proviso that a and b are not both 0,

-   -   -    optionally includes 1 or 2 nitrogens as heteroatoms on the            phenyl residue,        -   the carbons of the heteroaryl group are each independently            optionally substituted with a substituent selected from the            group consisting of halogen, —OH, —CN, —NO₂, halogen, C₁ to            C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle,            aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,            carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and            amino,        -   the nitrogens, if present, of the heteroaryl group are each            independently optionally substituted with a substituent            selected from the group consisting of —OH, C₁ to C₁₂ alkyl,            C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl,            heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,            carbamoyl, substituted sulfonyl, sulfonate and sulfonamide,        -   a and b are independently 1, 2, or 3.        -   c and d are independently 1 or 2,        -   n and p are independently 0, 1, 2 or 3,        -   k is 0, 1, or 2,        -   each R is independently selected from the group consisting            of hydrogen, halogen, —OH, —CN, —NO₂, halogen, C₁ to C₁₂            alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl,            heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,            carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and            amino,        -   each R^(N) is independently selected from the group            consisting of hydrogen, —OH, C₁ to C₁₂ alkyl, C₁ to C₁₂            heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl,            aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,            substituted sulfonyl, sulfonate and sulfonamide, and        -   wherein B may be attached to either side of A′ so that in            the example of A′ being

-   -   -    the W—B-A′ can be

-   -   B and B′ are each independently a 4- to 8-membered ring that is        an aryl, heteroaryl, cycloalkyl, or heterocycle, wherein each        hetero atom, if present, is independently N, O or S and wherein        at least one of B or B′ is aromatic;    -   each R^(a) is independently selected from the group consisting        of —OH, —CN, —NO₂, halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂        heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,        alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted        sulfonyl, sulfonate, sulfonamide and amino; and if B or B′ is        not aromatic, it may also be substituted with one or more oxo;    -   each r is independently 0, 1, 2 or 3;    -   W is independently selected from

-   -   -   wherein:        -   X¹ is CH₂, NH, O or S,        -   Y¹, Y² and Z¹ are each independently CH or N,        -   X² is NH, O or S,        -   V is —CH₂—CH₂—, —CH═CH—, —N═CH—,            —(CH₂)_(a)—N(R^(N))—(CH₂)_(b)— or —(CH₂)_(a)—O—(CH₂)_(b)—,            wherein a and b are independently 0, 1, 2, or 3 with the            proviso that a and b are not both 0,

-   -   -    optionally includes 1 or 2 nitrogens as heteroatoms on the            phenyl residue,        -   W is optionally substituted with one or more substituents            selected from the group consisting of —OH, —CN, —NO₂,            halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl,            heterocycle, aryl, heteroaryl, aralkyl, alkoxy,            alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl,            sulfonate, sulfonamide and amino,        -   W and ring B′ can be connected through either a carbon or a            nitrogen atom on B′, and        -   Cy is a monocyclic, bicyclic or tricyclic 5- to 12-membered            cycloalkyl, heterocycle, aryl group or heteroaryl group            wherein up to three heteroatoms are independently N, S or O            and which is optionally substituted with one or more            substituents selected from the group consisting of —OH, —CN,            —NO₂, halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl,            cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,            alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl,            sulfonate, sulfonamide and amino;

    -   each R^(c), R^(d), R^(e) and R^(f) is independently selected        from the group consisting of: hydrogen, C₁ to C₈ alkyl, C₁ to C₈        heteroalkyl, aralkyl and a 4- to 8-membered ring which may be        cycloalkyl, heterocycle, heteroaryl or aryl, wherein, each        hetero atom, if present, is independently N, O or S,        -   each of R^(c), R^(d), R^(e) and R^(f) may optionally be            substituted by C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,            aralkyl, or a 4- to 8-membered ring which may be cycloalkyl,            heterocycle, heteroaryl or aryl and wherein each heteroatom,            if present, is independently N, O or S,        -   R^(c) and R^(d) are optionally joined to form a 4- to            8-membered heterocycle which is optionally fused to another            3- to 5-membered heterocycle or heteroaryl ring, and        -   R^(e) and R^(f) are optionally joined to form a 4- to            8-membered heterocycle which is optionally fused to another            3- to 5-membered heterocycle or heteroaryl ring;

    -   Y and Y′ are each independently carbon or nitrogen; and

    -   Z and Z′ are independently selected from the group consisting of        hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl, cycloalkyl,        heterocycle, aryl, heteroaryl, aralkyl, 1-3 amino acids,        —[U—(CR⁴ ₂)_(t)—NR⁵—C(R⁴ ₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴        ₂)_(t)—R⁸, —U—(CR⁴ ₂)_(t)—R⁸, and —[U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴        ₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—O—(CR⁴ ₂)_(t)—R⁸, wherein,        -   U is selected from the group consisting of —C(O)—, —C(S)—            and —S(O)₂—,        -   each R⁴, R⁵ and R⁷ is independently selected from the group            consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈            heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and            aralkyl,        -   R⁸ is selected from the group consisting of hydrogen, C₁ to            C₈ alkyl, C₁ to C₈ heteroalkyl, cycloalkyl, heterocycle,            aryl, heteroaryl, aralkyl, —C(O)—R⁸¹, —C(S)—R⁸¹,            —C(O)—O—R⁸¹, —C(O)—N—R⁸¹ ₂, —S(O)₂—R⁸¹ and —S(O)₂—N—R⁸¹ ₂,            wherein each R⁸¹ is independently chosen from the group            consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈            heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and            aralkyl,        -   optionally, R¹ and R⁸ together form a 4-7 membered ring,        -   each t is independently 0, 1, 2, 3, or 4, and        -   u is 0, 1, or 2.

In a first embodiment of the first aspect, A′ is selected from the groupconsisting of a single bond, —(CR₂)_(n)—O—(CR₂)_(p)—,—(CR₂)_(n)—N(R^(N))—(CR₂)_(p)—, —(CR₂)_(n)—C(O)—N(R^(N))—(CR₂)_(p)—,—(CR₂)_(n)—N(R^(N))—C(O)—N(R^(N))—(CR₂)_(p)— and—(CR₂)_(n)—N(R^(N))—C(O)—O—(CR₂)_(p)— and a heteroaryl group selectedfrom the group consisting of

In a second embodiment of the first aspect, A′ is selected from thegroup consisting of a single bond,

In a third embodiment of the first aspect, R^(c), R^(d), R^(e) and R^(f)are each independently selected from the group consisting of: hydrogen,C₁ to C₈ alkyl and C₁ to C₈ heteroalkyl, wherein,

-   -   each hetero atom, if present, is independently N, O or S,    -   R^(c) and R^(d) are optionally joined to form a 4- to 8-membered        heterocycle which is optionally fused to another 3- to        6-membered heterocycle, and    -   R^(e) and R^(f) are optionally joined to form a 4- to 8-membered        heterocycle which is optionally fused to another 3- to        6-membered heterocycle.

In a fourth embodiment of the first aspect, R^(c) and R^(d) or R^(e) andR^(f) are optionally joined to form a 4- to 8-membered heterocycle whichis optionally fused to another 3- to 6-membered heterocycle.

In a fifth embodiment of the first aspect, R^(c) and R^(d) are joinedand form a heterocyclic fused ring system selected from the groupconsisting of:

wherein R^(N) is selected from the group consisting of hydrogen, —OH, C₁to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl,heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,substituted sulfonyl, sulfonate and sulfonamide.

In a sixth embodiment of the first aspect, R^(e) and R^(f) are joinedand form a heterocyclic fused ring system selected from the groupconsisting of:

wherein R^(N) is selected from the group consisting of hydrogen, —OH, C₁to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl,heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,substituted sulfonyl, sulfonate and sulfonamide.

In a seventh embodiment of the first aspect, B and B′ together isselected from the group consisting of

wherein

-   -   each X is independently N or C and if C, may include a hydrogen        as necessary to complete the valence shell;    -   each X′ is independently —N— or —CH—, with the proviso that no        more than two X′ are —N—;    -   each Y is independently selected from —CH₂—, —NH—, —O—, —S—,        —C(O)₂—, or —S(O)₁₋₂—; and    -   B and B′ attach to the remainder of the compound at any        available attachment point on the molecule.

In an eighth embodiment of the first aspect, B and B′ together

wherein * indicates attachment points to the remainder of the compound.

In a ninth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compound.

In a tenth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compoundwherein no more than 2 of X are nitrogen.

In an eleventh embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compoundand R^(N) is selected from the group consisting of hydrogen, —OH, C₁ toC₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl,heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,substituted sulfonyl, sulfonate and sulfonamide.

In a twelfth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compoundand R^(N) is selected from the group consisting of hydrogen, —OH, C₁ toC₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl,heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,substituted sulfonyl, sulfonate and sulfonamide.

In a thirteenth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compoundand R^(N) is selected from the group consisting of hydrogen, —OH, C₁ toC₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl,heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,substituted sulfonyl, sulfonate and sulfonamide.

In a fourteenth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compoundand the six-membered ring optionally contains one or two additionalnitrogens as heteroatoms with the proviso that the total number ofnitrogens in the six-membered ring does not exceed two.

In a fifteenth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compoundand the phenyl moiety optionally contains one or two nitrogens asheteroatoms.

In a sixteenth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compound;the phenyl moiety optionally contains one or two nitrogens asheteroatoms; and R^(N) is selected from the group consisting ofhydrogen, —OH, C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl,heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl,alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.

In a second aspect of the invention, compounds have formula II:

wherein A′ is selected from the group consisting of a single bond,

In a first embodiment of the second aspect, compounds have formula IIwherein A′ is

In a second embodiment of the second aspect, compounds have formula IIa:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a third embodiment of the second aspect, compounds have formula IIawherein A′ is

In a fourth embodiment of the second aspect, compounds have formula IIb:

wherein each X^(b) and X^(c) is independently C or N.

In a fifth embodiment of the second aspect, compounds have formula IIbwherein A′ is

In a sixth embodiment of the second aspect, compounds have formula IIc:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH , —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a seventh embodiment of the second aspect, compounds have formula IIcwherein A′ is

In an eighth embodiment of the second aspect, compounds have formulaIId:

wherein each X^(b) and X^(c) is independently C or N.

In a ninth embodiment of the second aspect, compounds have formula IIdwherein A′ is

In a tenth embodiment of the second aspect, compounds have formula IIe:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In an eleventh embodiment of the second aspect, compounds have formulaIIe wherein A′ is

In a twelfth embodiment of the second aspect, compounds have formulaIIf:

wherein each X^(b) and X^(c) is independently C or N.

In a thirteenth embodiment of the second aspect, compounds have formulaIIf wherein A′ is

In a fourteenth embodiment of the second aspect, compounds have formulaIIg:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a fifteenth embodiment of the second aspect, compounds have formulaIIg wherein A′ is

In a sixteenth embodiment of the second aspect, compounds have formulaIIh:

wherein X^(c) and each X^(b)) is independently C or N.

In a seventeenth embodiment of the second aspect, compounds have formulaIIh wherein A′ is

In an eighteenth embodiment of the second aspect, compounds have formulaIIi:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a nineteenth embodiment of the second aspect, compounds have formulaIIi wherein A′ is

In a twentieth embodiment of the second aspect, compounds have formulaIIh or IIi wherein X^(c) is C.

In an twenty-first embodiment of the second aspect, compounds haveformula IIh or IIi wherein X^(c) is N.

In a twenty-second embodiment of the second aspect, compounds haveformula IIj:

wherein

-   -   X^(c) is —CH₂—, —NH— or —CH₂—CH₂—, and    -   each X^(b) is independently C or N.

In a twenty-third embodiment of the second aspect, compounds haveformula IIj wherein A′ is

In a twenty-fourth embodiment of the second aspect, compounds haveformula IIk:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a twenty-fifth embodiment of the second aspect, compounds haveformula IIk wherein A′ is

In a twenty-sixth embodiment of the second aspect, compounds haveformula IIl:

wherein:

-   -   each X^(b) and X^(c) is independently C or N;    -   each R^(b) is selected from the group consisting of oxo, —OH,        —CN, —NO₂, halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl,        cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,        alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl,        sulfonate, sulfonamide and amino; and    -   s is 0, 1, 2, or 3.

In a twenty-seventh embodiment of the second aspect, compounds haveformula II. wherein A′ is

In a twenty-eighth embodiment of the second aspect, compounds haveformula IIm:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a twenty-ninth embodiment of the second aspect, compounds haveformula IIm wherein A′ is

In a thirtieth embodiment of the second aspect, compounds have formulaIIn:

wherein:

-   -   each X^(b) and X^(c) is independently C or N;    -   X^(b1) is N or O; and    -   X^(b2) is S(O)₂ or C(O).

In a thirty-first embodiment of the second aspect, compounds haveformula IIn wherein A′ is

In a thirty-second embodiment of the second aspect, compounds haveformula IIo:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a thirty-third embodiment of the second aspect, compounds haveformula IIo wherein A′ is

In an thirty-fourth embodiment of the second aspect, compounds haveformula IIp:

wherein:

-   -   each X^(b) and X^(c) is independently C or N;    -   X^(b1) is N or O; and    -   X^(b2) is S(O)₂ or C(O).

In a thirty-fifth embodiment of the second aspect, compounds haveformula IIp wherein A′ is

In a thirty-sixth embodiment of the second aspect, compounds haveformula IIq:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a thirty-seventh embodiment of the second aspect, compounds haveformula IIq wherein A′ is

In a third aspect of the invention, compounds have formula III:

wherein A′ is selected from the group consisting of a single bond,

And

each X^(c) is independently C or N.

In a first embodiment of the third aspect, compounds have formula IIIwherein A′ is

In a second embodiment of the third aspect, compounds have formula IIIa:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a third embodiment of the third aspect, compounds have formula IIIawherein A′ is

In a fourth embodiment of the third aspect, compounds have formula IIIb:

wherein each X^(b) is independently C or N.

In a fifth embodiment of the third aspect, compounds have formula IIIbwherein A′ is

In a sixth embodiment of the third aspect, compounds have formula IIIc:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a seventh embodiment of the third aspect, compounds have formula IIIcwherein A′ is

In an eighth embodiment of the third aspect, compounds have formulaIIId:

In a ninth embodiment of the third aspect, compounds have formula IIIe:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂', —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a tenth embodiment of the third aspect, compounds have formula IIIf:

In an eleventh embodiment of the third aspect, compounds have formulaIIIg:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a twelfth embodiment of the third aspect, compounds have formulaIIIh:

wherein each X^(b) is independently C or N.

In a thirteenth embodiment of the third aspect, compounds have formulaIIIh wherein A′ is

In a fourteenth embodiment of the third aspect, compounds have formulaIIIi:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a fifteenth embodiment of the third aspect, compounds have formulaIIIi wherein A′ is

In a sixteenth embodiment of the third aspect, compounds have formulaIIIj:

In a seventeenth embodiment of the third aspect, compounds have formulaIIIk:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In an eighteenth embodiment of the third aspect, compounds have formulaIIIl:

In a nineteenth embodiment of the third aspect, compounds have formulaIIIm:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a twentieth embodiment of the third aspect, compounds have formulaIII:

wherein each X^(b) is independently C or N.

In a twenty-first embodiment of the third aspect, compounds have formulaIIIn wherein A′ is

In a twenty-second embodiment of the third aspect, compounds haveformula IIIo:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a twenty-third embodiment of the third aspect, compounds have formulaIIIo wherein A′ is

In a twenty-fourth embodiment of the third aspect, compounds haveformula IIIp:

In a twenty-fifth embodiment of the third aspect, compounds have formulaIIIq:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a fourth aspect of the invention, compounds have formula IV:

wherein:

-   -   A′ is selected from the group consisting of a single bond,

and

-   -   each X^(b) and X^(c) is independently C or N.

In a first embodiment of the fourth aspect, compounds have formula IVwherein A′ is

In a second embodiment of the fourth aspect, compounds have formula IVa:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a third embodiment of the fourth aspect, compounds have formula IVawherein A′ is

In a fifth aspect of the invention, compounds have formula V:

wherein:

-   -   A′ is selected from the group consisting of a single bond,

and

-   -   each X^(c) is independently C or N with the proviso that no more        than two X^(c) are N.

In a first embodiment of the fifth aspect, compounds have formula Vwherein A′ is

In a second embodiment of the fifth aspect, compounds have formula Va:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a third embodiment of the fifth aspect, compounds have formula Vawherein A′ is

In a fourth embodiment of the fifth aspect, compounds have formula Vb:

wherein each X^(b) is independently C or N.

In a fifth embodiment of the fifth aspect, compounds have formula Vbwherein A′ is

In a sixth embodiment of the fifth aspect, compounds have formula Vc:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a seventh embodiment of the fifth aspect, compounds have formula Vcwherein A′ is

In an eighth embodiment of the fifth aspect, compounds have formula Vd:

In a ninth embodiment of the fifth aspect, compounds have formula Ve:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

In a sixth aspect of the invention, in any compound of any of the secondthrough fifth aspects, R^(c), R^(d), R^(e) an R^(f) are eachindependently selected from the group consisting of: hydrogen, C₁ to C₈alkyl and C₁ to C₈ heteroalkyl, wherein,

-   -   each hetero atom, if present, is independently N, O or S,    -   R^(c) and R^(d) are optionally joined to form a 4- to 8-membered        heterocycle which is optionally fused to another 3- to        6-membered heterocycle, and    -   R^(e) and R^(f) are optionally joined to form a 4- to 8-membered        heterocycle which is optionally fused to another 3- to        6-membered heterocycle.

In a first embodiment of the sixth aspect, R^(c) and R^(d) or R^(e) andR^(f) are joined to form a 4- to 8-membered heterocycle which isoptionally fused to another 3- to 6-membered heterocycle.

In a second embodiment of the sixth aspect, both of R^(c) and R^(d) andR^(e) and R^(f) are joined to form a 4- to 8-membered heterocycle whichis optionally fused to another 3- to 6-membered heterocycle.

In a seventh aspect of the invention, each R^(a), if present in any ofthe other aspects of the invention, is independently —CN, —OCHF₂, —CF₃,or —F.

In an eighth aspect of the invention, if present in any compound of anyof the other aspects, one of Y and Y′ is N.

In a first embodiment of the eighth aspect, both Y and Y′ are N.

In a ninth aspect of the invention, Z and Z′ in any of the previousaspects are each 1-3 amino acids.

In a first embodiment of the ninth aspect, the amino acids are in the Dconfiguration.

In a tenth aspect of the invention, Z and Z′ in any of the previousaspects are each independently selected from the group consisting of—[U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸,—U—(CR⁴ ₂)_(t)—R⁸ and —[U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)]_(u)—U—(CR⁴₂)_(t)—O—(CR⁴ ₂)_(t)—R⁸.

In a first embodiment of the tenth aspect, both of Z and Z′ are —[U—(CR⁴₂)_(t)—NR⁵—(CR⁴ ₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸.

In a second embodiment of the tenth aspect, one or both of Z and Z′ are—U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸.

In a third embodiment of the tenth aspect, one or both of Z and Z′ are—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸.

In a fourth embodiment of the tenth aspect, one or both of Z and Z′ are—[C(O)—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴₂)_(t)—R⁸.

In a fifth embodiment of the tenth aspect, one or both of Z and Z′ are—C(O)—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸.

In a sixth embodiment of the tenth aspect, one or both of Z and Z′ are—[C(O)—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)]_(u)—C(O)—(CR⁴ ₂)_(t)—NR⁷—(CR⁴₂)_(t)—R⁸.

In a seventh embodiment of the tenth aspect, one or both of Z and Z′ are—C(O)—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)—C(O)—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸.

In an eighth embodiment of the tenth aspect, one or both of Z and Z′ are—C(O)—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸.

In a ninth embodiment of the tenth aspect, one or both of Z and Z′ are—C(O)—(CR⁴ ₂)_(n)—NR⁷—(CR⁴ ₂)_(n)—C(O)—R⁸¹.

In a tenth embodiment of the tenth aspect, one or both of Z and Z′ are—C(O)—(CR⁴ ₂)_(n)—NR⁷—C(O)—R⁸¹.

In an eleventh embodiment of the tenth aspect, one or both of Z and Z′are —C(O)—(CR⁴ ₂)_(n)—NR⁷—(CR⁴ ₂)_(n)—C(O)—O—R⁸¹.

In a twelfth embodiment of the tenth aspect, one or both of Z and Z′ are—C(O)—(CR⁴ ₂)_(n)—NR⁷—C(O)—O—R⁸¹.

In a thirteenth embodiment of the tenth aspect, one or both of Z and Z′are —U—(CR⁴ ₂)_(t)—R⁸.

In a fourteenth embodiment of the tenth aspect, one or both of Z and Z′are —C(O)—(CR⁴ ₂)_(t)—R⁸.

In a fifteenth embodiment of the tenth aspect, one or both of Z and Z′are —[U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—O—(CR⁴ ₂)_(t)—R⁸.

In a sixteenth embodiment of the tenth aspect, one or both of Z and Z′are —U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)—U—(CR⁴ ₂)_(t)—O—(CR⁴ ₂)_(t)—R⁸.

In a seventeenth embodiment of the tenth aspect, one or both of Z and Z′are —C(O)—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)—C(O)—(CR⁴ ₂)_(t)—O—(CR⁴ ₂)_(t)—R⁸.

In an eighteenth embodiment of the tenth aspect, one or both of Z and Z′are —U—(CR⁴ ₂)_(t)—O—(CR⁴ ₂)_(t)—R⁸.

An eleventh aspect of the invention provides a pharmaceuticalcomposition comprising the compounds of the invention.

A twelfth aspect of the invention provides use of the compounds of theinvention in the manufacture of a medicament.

In a first embodiment of the twelfth aspect, the medicament is for thetreatment of hepatitis C.

A thirteenth aspect of the invention provides a method of treatinghepatitis C comprising administering to a subject in need thereof, atherapeutically effective amount of any one of the compounds of theinvention.

DETAILED DESCRIPTION

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Definition ofstandard chemistry terms may be found in reference works, includingCarey and Sundberg (2007) “Advanced Organic Chemistry 5^(th) Ed.” Vols.A and B, Springer Science+Business Media LLC, New York. The practice ofthe present invention will employ, unless otherwise indicated,conventional methods of synthetic organic chemistry, mass spectroscopy,preparative and analytical methods of chromatography, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology.

The term “alkanoyl” as used herein contemplates a carbonyl group with alower alkyl group as a substituent.

The term “alkenyl” as used herein contemplates substituted orunsubstituted, straight and branched chain alkene radicals, includingboth the E- and Z-forms, containing from two to eight carbon atoms. Thealkenyl group may be optionally substituted with one or moresubstituents selected from the group consisting of halogen, —CN, —NO₂,CO₂R, C(O)R, —O—R, —N(R^(N))₂, —N(R^(N))C(O)R, —N(R^(N))S(O)₂R, —SR,—C(O)N(R^(N))₂, —OC(O)R, —OC(O)N(R^(N))₂, S(O)R, SO₂R, —SO₃R,—S(O)₂N(R^(N))₂, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryland heteroaryl.

The term “alkoxy” as used herein contemplates an oxygen with a loweralkyl group as a substituent and includes methoxy, ethoxy, butoxy,trifluoromethoxy and the like. It also includes divalent substituentslinked to two separated oxygen atoms such as, without limitation,—O—(CH₂)₁₋₄—O—, —O—CF₂—O—, —O—(CH₂)₁₋₄—O—(CH₂CH₂—O)₁₋₄— and—(O—CH₂CH₂—O)₁₋₄—.

The term “alkoxycarbonyl” as used herein contemplates a carbonyl groupwith an alkoxy group as a substituent.

The term “alkyl” as used herein contemplates substituted orunsubstituted, straight and branched chain alkyl radicals containingfrom one to fifteen carbon atoms. The term “lower alkyl” as used hereincontemplates both straight and branched chain alkyl radicals containingfrom one to six carbon atoms and includes methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl and the like. The alkyl group maybe optionally substituted with one or more substituents selected fromhalogen, —CN, —NO₂, —C(O)₂R, —C(O)R, —O—R, —N(R^(N))₂, —N(R^(N))C(O)R,—N(R^(N))S(O)₂R,

—SR, —C(O)N(R^(N))₂, —OC(O)R, —OC(O)N(R^(N))₂, —SOR, —SO₂R, —SO₃R,—S(O)₂N(R^(N))₂, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryland heteroaryl.

The term “alkylene,” “alkenylene” and “alkynylene” as used herein refersto the groups “alkyl,” “alkenyl” and “alkynyl” respectively, when theyare divalent, ie, attached to two atoms.

The term “alkylsulfonyl” as used herein contemplates a sulfonyl groupwhich has a lower alkyl group as a substituent.

The term “alkynyl” as used herein contemplates substituted orunsubstituted, straight and branched carbon chain containing from two toeight carbon atoms and having at least one carbon-carbon triple bond.The term alkynyl includes, for example ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 3-methyl-1-butynyl and the like. The alkynyl group may beoptionally substituted with one or more substituents selected from halo,—CN, NO₂, CO₂R, C(O)R, —O—R, —N(R^(N))₂, —N(R^(N))C(O)R,—N(R^(N))S(O)₂R, —SR, —C(O)N(R^(N))₂, —OC(O)R, —OC(O)N(R^(N))₂, —SOR,—SO₂R, —SO₃R, —S(O)₂N(R^(N))₂, phosphate, phosphonate, cycloalkyl,cycloalkenyl, aryl and heteroaryl.

The term “amino” as used herein contemplates a group of the structure—NR^(N) ₂.

The term “amino acid” as used herein contemplates a group of thestructure

in either the D or the L configuration and includes but is not limitedto the twenty “standard” amino acids: isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophan, valine, alanine,asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline,serine, tyrosine, arginine and histidine. The present invention alsoincludes, without limitation, D-configuration amino acids, beta-aminoacids, amino acids having side chains as well as all non-natural aminoacids known to one skilled in the art.

The term “aralkyl” as used herein contemplates a lower alkyl group whichhas as a substituent an aromatic group, which aromatic group may besubstituted or unsubstituted. The aralkyl group may be optionallysubstituted with one or more substituents selected from halogen, —CN,—NO₂, —CO₂R, —C(O)R, —O—R, —N(R^(N))₂, —N(R^(N))C(O)R, —N(R^(N))S(O)₂R,—SR, —C(O)N(R^(N))₂, —OC(O)R, —OC(O)N(R^(N))₂, —SOR, —SO₃R,—S(O)₂N(R^(N))₂, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryland heteroaryl.

The terms “aryl,” “aromatic group” or “aromatic ring” as used hereincontemplates substituted or unsubstituted single-ring and multiplearomatic groups (for example, phenyl, pyridyl and pyrazole, etc.) andpolycyclic ring systems (naphthyl and quinolinyl, etc.). The polycyclicrings may have two or more rings in which two atoms are common to twoadjoining rings (the rings are “fused”) wherein at least one of therings is aromatic, e.g., the other rings can be cycloalkyls,cycloalkenyls, aryl, heterocycles and/or heteroaryls. The aryl group maybe optionally substituted with one or more substituents selected fromhalogen, alkyl, —CN, —NO₂, —CO₂R, —C(O)R, —O—R, —N(R^(N))₂,—N(R^(N))C(O)R, —N(R^(N))S(O)₂R, —SR, —C(O)N(R^(N))₂, —OC(O)R,—OC(O)N(R^(N))₂, —SOR, —SO₂R, —SO₃R, —S(O)₂N(R^(N))₂, —SiR₃, —P(O)R,phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

The term “arylsulfonyl” as used herein contemplates a sulfonyl groupwhich has as a substituent an aryl group. The term is meant to include,without limitation, monovalent as well as multiply valent aryls (eg,divalent aryls).

The term “carbamoyl” as used herein contemplates a group of thestructure

The term “carbonyl” as used herein contemplates a group of the structure

The term “carboxyl” as used herein contemplates a group of the structure

The term “cycloalkyl” as used herein contemplates substituted orunsubstituted cyclic alkyl radicals containing from three to twelvecarbon atoms and includes cyclopropyl, cyclopentyl, cyclohexyl and thelike. The term “cycloalkyl” also includes polycyclic systems having tworings in which two or more atoms are common to two adjoining rings (therings are “fused”). The cycloalkyl group may be optionally substitutedwith one or more substituents selected from halo, —CN, —NO₂, —CO₂R,—C(O)R, —O—R, —N(R^(N))₂, —N(R^(N))C(O)R, —N(R^(N))S(O)₂R, —SR,—C(O)N(R^(N))₂, —OC(O)R, —OC(O)N(R^(N))₂, —SOR, —SO₂R, —S(O)₂N(R^(N))₂,phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl.

The term “cycloalkenyl” as used herein contemplates substituted orunsubstituted cyclic alkenyl radicals containing from four to twelvecarbon atoms in which there is at least one double bond between two ofthe ring carbons and includes cyclopentenyl, cyclohexenyl and the like.The term “cycloalkenyl” also includes polycyclic systems having tworings in which two or more atoms are common to two adjoining rings (therings are “fused”). The cycloalkenyl group may be optionally substitutedwith one or more substituents selected from halo, —CN, —NO₂, —CO₂R,—C(O)R, —O—R, —N(R^(N))₂, —N(R^(N))C(O)R, —N(R^(N))S(O)₂R, —SR,—C(O)N(R^(N))₂, —OC(O)R, —OC(O)N(R^(N))₂, —SOR, —SO₂R, —S(O)₂N(R^(N))₂,phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl.

The term “halo” or “halogen” as used herein includes fluorine, chlorine,bromine and iodine.

The term “heteroalkyl” as used herein contemplates an alkyl with one ormore hctcroatoms.

The term “heteroatom”, particularly within a ring system, refers to N, Oand S.

The term “heterocyclic group,” “heterocycle” or “heterocyclic ring” asused herein contemplates substituted or unsubstituted aromatic andnon-aromatic cyclic radicals having at least one heteroatom as a ringmember. Preferred heterocyclic groups are those containing five or sixring atoms which includes at least one hetero atom and includes cyclicamines such as morpholino, piperidino, pyrrolidino and the like andcyclic ethers, such as tetrahydrofuran, tetrahydropyran and the like.Aromatic heterocyclic groups, also termed “heteroaryl” groups,contemplates single-ring hetero-aromatic groups that may include fromone to three heteroatoms, for example, pyrrole, furan, thiophene,imidazole, oxazole, thiazole, triazole, pyrazole, oxodiazole,thiadiazole, pyridine, pyrazine, pyridazine, pyrimidine and the like.The term heteroaryl also includes polycyclic hetero-aromatic systemshaving two or more rings in which two or more atoms are common to twoadjoining rings (the rings are “fused”) wherein at least one of therings is a heteroaryl, e.g., the other rings can be cycloalkyls,cycloalkenyls, aryl, heterocycles and/or heteroaryls. Examples ofpolycyclic heteroaromatic systems include quinoline, isoquinoline,cinnoline, tetrahydroisoquinolinc, quinoxaline, quinazoline,benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole,indazole, purine, benzotriazole, pyrrolepyridine, pyrrazolopyridine andthe like. The heterocyclic group may be optionally substituted with oneor more substituents selected from the group consisting of halo, alkyl,—CN, —NO₂, —CO₂R, —C(O)R, —O—R, —N(e)₂, —N(R^(N))C(O)R, —N(R^(N))S(O)₂R,—SR, —C(O)N(R^(N))₂, —OC(O)R, —OC(O)N(R^(N))₂, —SOR, —SO₂R, —SO₃R,—S(O)₂N(R^(N))₂, —SiR₃, —P(O)R, phosphate, phosphonate, cycloalkyl,cycloalkenyl, aryl and heteroaryl.

The term “oxo” as used herein contemplates an oxygen atom attached witha double bond.

By “pharmaceutically acceptable” or “pharmacologically acceptable” ismeant a material which is not biologically or otherwise undesirable,i.e., the material may be administered to an individual without causingany undesirable biological effects or interacting in a deleteriousmanner with any of the components of the composition in which it iscontained.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention which is made with counterions understood in the art to begenerally acceptable for pharmaceutical uses and which possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine,morpholine, piperidine, dimethylamine, diethylamine and the like. Alsoincluded are salts of amino acids such as arginates and the like andsalts of organic acids like glucurmic or galactunoric acids and the like(see, e.g., Berge et al., 1977, J. Pharm. Sci. 66:1-19).

The terms “phosphate” and “phosphonate” as used herein refer to themoieties having the following structures, respectively:

The terms “salts” and “hydrates” refers to the hydrated forms of thecompound that would favorably affect the physical or pharmacokineticproperties of the compound, such as solubility, palatability,absorption, distribution, metabolism and excretion. Other factors, morepractical in nature, which those skilled in the art may take intoaccount in the selection include the cost of the raw materials, case ofcrystallization, yield, stability, solubility, hygroscopicity,flowability and manufacturability of the resulting bulk drug.

The term sulfonamide as used herein contemplates a group having thestructure

The term “sulfonate” as used herein contemplates a group having thestructure

wherein R^(s) is selected from the group consisting of hydrogen, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ alkanoyl, or C₁-C₁₀alkoxycarbonyl.

The term “sulfonyl” as used herein contemplates a group having thestructure

“Substituted sulfonyl” as used herein contemplates a group having thestructure

including, but not limited to alkylsulfonyl and arylsulfonyl.

The term “thiocarbonyl,” as used herein, means a carbonyl wherein anoxygen atom has been replaced with a sulfur.

Each R is independently selected from hydrogen, —OH, —CN, —NO₂, halogen,C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl,alkanoyl, carbamoyl, substituted sulfonyl, sulfonatc, sulfonamide,amino, and oxo.

Each R^(N) is independently selected from the group consisting ofhydrogen, —OH, C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate andsulfonamide. Two R^(N) may be taken together with C, O, N or S to whichthey are attached to form a five to seven membered ring which mayoptionally contain a further heteroatom.

The compounds of the present invention may be used to inhibit or reducethe activity of HCV, particularly HCV's NS5A protein. In these contexts,inhibition and reduction of activity of the NS5A protein refers to alower level of the measured activity relative to a control experiment inwhich the cells or the subjects are not treated with the test compound.In particular aspects, the inhibition or reduction in the measuredactivity is at least a 10% reduction or inhibition. One of skill in theart will appreciate that reduction or inhibition of the measuredactivity of at least 20%, 50%, 75%, 90% or 100%, or any number inbetween, may be preferred for particular applications.

In a first aspect, compounds of formula I are provided:

wherein:

-   -   A′ is selected from the group consisting of single bond,        —(CR₂)_(n)—C(O)—(CR₂)_(p)—, —(CR₂)_(n)—O—(CR₂)_(p)—,        —(CR₂)_(n)—N(R^(N))—(CR₂)_(p)—,        —(CR₂)_(n)—S(O)_(k)—N(R^(N))—(CR₂)_(p)—,        —(CR₂)_(n)—C(O)—N(R^(N))—(CR₂)_(p)—,        —(CR₂)_(n)—N(R^(N))—C(O)—N(R^(N))—(CR₂)_(P)—,        —(CR₂)_(n)—C(O)—O—(CR₂)_(p)—,        —(CR₂)_(n)—N(R^(N))—S(O)_(k)—N(R^(N))—(CR₂)_(p)— and        —(CR₂)_(n)—N(R^(N))—C(O)—O—(CR₂)_(p)— and a heteroaryl group        selected from the group consisting of

-   -    wherein:        -   X¹ is CH₂, NH, O or S,        -   Y¹, Y² and Z¹ are each independently CH or N,        -   X² is NH, O or S,        -   V is —CH₂—CH₂—, —CH═CH—, —N═CH—,            (CH₂)_(a)—N(R^(N))—(CH₂)_(b)— or —(CH₂)_(a)—O—(CH₂)_(b)—,            wherein a and b are independently 0, 1, 2, or 3 with the            proviso that a and b are not both 0,

-   -   -    optionally includes 1 or 2 nitrogens as heteroatoms on the            phenyl residue,        -   the carbons of the heteroaryl group are each independently            optionally substituted with a substituent selected from the            group consisting of halogen, —OH, —CN, —NO₂, halogen, C₁ to            C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle,            aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,            carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and            amino, the nitrogens, if present, of the heteroaryl group            are each independently optionally substituted with a            substituent selected from the group consisting of —OH, C₁ to            C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle,            aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,            carbamoyl, substituted sulfonyl, sulfonate and sulfonamide,        -   a and b are independently 1, 2, or 3.        -   c and d are independently 1 or 2,        -   n and p are independently 0, 1, 2 or 3,        -   k is 0, 1, or 2,        -   each R is independently selected from the group consisting            of hydrogen, halogen, —OH, —CN, —NO₂, halogen, C₁ to C₁₂            alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl,            heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,            carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and            amino,        -   each R^(N) is independently selected from the group            consisting of hydrogen, —OH, C₁ to C₁₂ alkyl, C₁ to C₁₂            heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl,            aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,            substituted sulfonyl, sulfonate and sulfonamide and        -   wherein B may be attached to either side of A′ so that in            the example of A′ being

-   -   -    the W—B-A′ can be

-   -   B and B′ are each independently a 4- to 8-membered ring that is        an aryl, heteroaryl, cycloalkyl, or heterocycle, wherein each        hetero atom, if present, is independently N, O or S and wherein        at least one of B or B′ is aromatic;    -   each R^(a) is independently selected from the group consisting        of —OH, —CN, —NO₂, halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂        heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,        alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted        sulfonyl, sulfonate, sulfonamide and amino; and if B or B′ is        not aromatic, it may also be substituted with one or more oxo;    -   each r is independently 0, 1, 2 or 3;    -   W is independently selected from

-   -   -   wherein:        -   X¹ is CH₂, NH, O or S,        -   Y¹, Y² and Z¹ are each independently CH or N,        -   X² is NH, O or S,        -   V is —CH₂—CH₂—, —CH═CH—, —N═CH—,            (CH₂)_(a)—N(R^(N))—(CH₂)_(b)— or —(CH₂)_(a)—O—(CH₂)_(b)—,            wherein a and b are independently 0, 1, 2, or 3 with the            proviso that a and b are not both 0,

-   -   -   optionally includes 1 or 2 nitrogens as heteroatoms on the            phenyl residue,        -   W is optionally substituted with one or more substituents            selected from the group consisting of —OH, —CN, —NO₂,            halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl,            heterocycle, aryl, heteroaryl, aralkyl, alkoxy,            alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl,            sulfonate, sulfonamide and amino,        -   W and ring B′ can be connected through either a carbon or a            nitrogen atom on B′, and        -   Cy is a monocyclic, bicyclic or tricyclic 5- to 12-membered            cycloalkyl, heterocycle, aryl group or heteroaryl group            wherein up to three heteroatoms are independently N, S or O            and which is optionally substituted with one or more            substituents selected from the group consisting of —OH, —CN,            —NO₂, halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl,            cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,            alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl,            sulfonate, sulfonamide and amino;

    -   each R^(c), R^(d), R^(e) and R^(f) is independently selected        from the group consisting of: hydrogen, C₁ to C₈ alkyl, C₁ to C₈        heteroalkyl, aralkyl and a 4- to 8-membered ring which may be        cycloalkyl, heterocycle, heteroaryl or aryl, wherein,        -   each hetero atom, if present, is independently N, O or S,        -   each of R^(c), R^(d), R^(e) and R^(f) may optionally be            substituted by C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,            aralkyl, or a 4- to 8-membered ring which may be cycloalkyl,            heterocycle, heteroaryl or aryl and wherein each heteroatom,            if present, is independently N, O or S,        -   R^(c) and R^(d) are optionally joined to form a 4- to            8-membered heterocycle which is optionally fused to another            3- to 5-membered heterocycle or heteroaryl ring, and        -   R^(e) and R^(f) are optionally joined to form a 4- to            8-membered heterocycle which is optionally fused to another            3- to 5-membered heterocycle or heteroaryl ring;

    -   Y and Y′ are each independently carbon or nitrogen; and

    -   Z and Z′ are independently selected from the group consisting of        hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl, cycloalkyl,        heterocycle, aryl, heteroaryl, aralkyl, 1-3 amino acids,        —[U—(CR⁴ ₂)_(t)—NR⁵—C(R⁴ ₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴        ₂)_(t)—R⁸, —U—(CR⁴ ₂)_(t)—R⁸, and —[U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴        ₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—O—(CR⁴ ₂)_(t)—R⁸, wherein,        -   U is selected from the group consisting of —C(O)—, —C(S)—            and —S(O)₂—,        -   each R⁴, R⁵ and R⁷ is independently selected from the group            consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈            heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and            aralkyl,        -   R⁸ is selected from the group consisting of hydrogen, C₁ to            C₈ alkyl, C₁ to C₈ heteroalkyl, cycloalkyl, heterocycle,            aryl, heteroaryl, aralkyl, —C(O)—R⁸¹, —C(S)—R⁸¹,            —C(O)—O—R⁸¹, —C(O)—N—R⁸¹ ₂, —S(O)₂—R⁸¹ and —S(O)₂—N—R⁸¹ ₂,            wherein each R⁸¹ is independently chosen from the group            consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈            heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and            aralkyl,        -   optionally, R⁷ and R⁸ together form a 4-7 membered ring,        -   each t is independently 0, 1, 2, 3, or 4, and        -   u is 0, 1, or 2.

The compounds of the present invention include pharmaceuticallyacceptable salts of I as well as an optically pure enantiomer, racemateor diastereomeric mixtures thereof.

In a first embodiment of the first aspect, A′ is selected from the groupconsisting of a single bond, —(CR₂)_(n)—O—(CR₂)_(p)—,—(CR₂)_(n)—N(R^(N))—(CR₂)_(p)—, —(CR₂)_(n)—C(O)—N(R^(N))—(CR₂)_(p)—,—(CR₂)_(n)—N(R^(N))—C(O)—N(R^(N))—(CR₂)_(p)— and—(CR₂)_(n)—N(R^(N))—C(O)—O—(CR₂)_(p)— and a heteroaryl group selectedfrom the group consisting of

In a second embodiment of the first aspect, A′ is selected from thegroup consisting of a single bond,

In a third embodiment of the first aspect, R^(c), R^(d), R^(e) and R^(f)are each independently selected from the group consisting of: hydrogen,C₁ to C₈ alkyl and C₁ to C₈ heteroalkyl, wherein,

-   -   each hetero atom, if present, is independently N, O or S,    -   R^(c) and R^(d) are optionally joined to form a 4- to 8-membered        heterocycle which is optionally fused to another 3- to        6-membered heterocycle, and    -   R^(e) and R^(f) are optionally joined to form a 4- to 8-membered        heterocycle which is optionally fused to another 3- to        6-membered heterocycle.

In a fourth embodiment of the first aspect, R^(c) and R^(d) or R^(e) andR^(f) are optionally joined to form a 4- to 8-membered heterocycle whichis optionally fused to another 3- to 6-membered heterocycle.

In a fifth embodiment of the first aspect, R^(c) and R^(d) are joinedand form a heterocyclic fused ring system selected from the groupconsisting of:

wherein R^(N) is selected from the group consisting of hydrogen, —OH, C₁to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl,heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,substituted sulfonyl, sulfonate and sulfonamide.

In a sixth embodiment of the first aspect, R^(e) and R^(f) are joinedand form a heterocyclic fused ring system selected from the groupconsisting of:

wherein R^(N) is selected from the group consisting of hydrogen, —OH, C₁to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl,heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,substituted sulfonyl, sulfonate and sulfonamide.

In a seventh embodiment of the first aspect, B and B′ together isselected from the group consisting of wherein

-   -   each X is independently N or C and if C, may include a hydrogen        as necessary to complete the valence shell;    -   each X′ is independently —N— or —CH—, with the proviso that no        more than two X′ are —N—;    -   each Y is independently selected from —CH₂—, —NH—, —O—, —S—,        —C(O)₂—, or —S(O)₁₋₂—; and    -   B and B′ attach to the remainder of the compound at any        available attachment point on the molecule.

In an eighth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compound.

In a ninth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compound.

In a tenth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compoundwherein no more than 2 of X are nitrogen.

In an eleventh embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compoundand R^(N) is selected from the group consisting of hydrogen, —OH, C₁ toC₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl,heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,substituted sulfonyl, sulfonate and sulfonamide.

In a twelfth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compoundand R^(N) is selected from the group consisting of hydrogen, —OH, C₁ toC₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl,heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,substituted sulfonyl, sulfonate and sulfonamide.

In a thirteenth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compoundand R^(N) is selected from the group consisting of hydrogen, —OH, C₁ toC₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl,heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,substituted sulfonyl, sulfonate and sulfonamide.

In a fourteenth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compoundand the six-membered ring optionally contains one or two additionalnitrogens as heteroatoms with the proviso that the total number ofnitrogens in the six-membered ring does not exceed two.

In a fifteenth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compoundand the phenyl moiety optionally contains one or two nitrogens asheteroatoms.

In a sixteenth embodiment of the first aspect, B and B′ together is

wherein * indicates attachment points to the remainder of the compound;the phenyl moiety optionally contains one or two nitrogens asheteroatoms; and R^(N) is selected from the group consisting ofhydrogen, —OH, C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, cycloalkyl,heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl,alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.

In a second aspect of the invention, compounds have formula II:

wherein A′ is selected from the group consisting of a single bond,

In a first embodiment of the second aspect, compounds have formula IIwherein A′ is

In a second embodiment of the second aspect, compounds have formula IIa:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIa as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a third embodiment of the second aspect, compounds have formula IIawherein A′ is

In a fourth embodiment of the second aspect, compounds have formula IIb:

wherein each X^(b) and X^(c) is independently C or N.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIb as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a fifth embodiment of the second aspect, compounds have formula IIbwherein A′ is

In a sixth embodiment of the second aspect, compounds have formula IIc:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of He as well as an optically pure enantiomer, racemateor diastereomeric mixtures thereof.

In a seventh embodiment of the second aspect, compounds have formula IIcwherein A′ is

In an eighth embodiment of the second aspect, compounds have formulaIId:

wherein each X^(b) and X^(c) is independently C or N.

The compounds of the present invention include pharmaceuticallyacceptable salts of IId as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a ninth embodiment of the second aspect, compounds have formula IIdwherein A′ is

In a tenth embodiment of the second aspect, compounds have formula IIe:

wherein

X and X′ are each independently selected from the group consisting of abond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—, —CH₂O—, —CH₂S—,—CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen from the groupconsisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of He as well as an optically pure enantiomer, racemateor diastereomeric mixtures thereof.

In an eleventh embodiment of the second aspect, compounds have formulaIIe wherein A′ is

In a twelfth embodiment of the second aspect, compounds have formulaIIf:

wherein each X^(b) and X^(c) is independently C or N.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIf as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a thirteenth embodiment of the second aspect, compounds have formulaIIf wherein A′ is

In a fourteenth embodiment of the second aspect, compounds have formulaIIg:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIg as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a fifteenth embodiment of the second aspect, compounds have formulaIIg wherein A′ is

In a sixteenth embodiment of the second aspect, compounds have formulaIIh:

wherein X^(c) and each X^(b) is independently C or N.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIh as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a seventeenth embodiment of the second aspect, compounds have formulaIIh wherein A′ is

In an eighteenth embodiment of the second aspect, compounds have formulaIIi:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of III as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a nineteenth embodiment of the second aspect, compounds have formulaIIi wherein A′ is

In a twentieth embodiment of the second aspect, compounds have formulaIIh or IIi wherein X^(c) is C.

In an twenty-first embodiment of the second aspect, compounds haveformula IIh or IIi wherein X^(c) is N.

In a twenty-second embodiment of the second aspect, compounds haveformula IIj:

wherein

-   -   X^(c) is —CH₂—, —NH— or —CH₂—CH₂—, and    -   each X^(b) is independently C or N.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIj as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a twenty-third embodiment of the second aspect, compounds haveformula IIj wherein A′ is

In a twenty-fourth embodiment of the second aspect, compounds haveformula IIk:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIk as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a twenty-fifth embodiment of the second aspect, compounds haveformula IIk wherein A′ is

In a twenty-sixth embodiment of the second aspect, compounds haveformula IIl:

wherein:

-   -   each X^(b) and X^(c) is independently C or N;    -   each R^(b) is selected from the group consisting of oxo, —OH,        —CN, —NO₂, halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl,        cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,        alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl,        sulfonate, sulfonamide and amino; and    -   s is 0, 1, 2, or 3.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIl as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a twenty-seventh embodiment of the second aspect, compounds haveformula IIl wherein A′ is

In a twenty-eighth embodiment of the second aspect, compounds haveformula IIm:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIm as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a twenty-ninth embodiment of the second aspect, compounds haveformula IIm wherein A′ is

In a thirtieth embodiment of the second aspect, compounds have formulaIIn:

wherein:

-   -   each X^(b) and X^(c) is independently C or N;    -   X^(b1) is N or O; and    -   X^(b2) is S(O)₂ or C(O).

The compounds of the present invention include pharmaceuticallyacceptable salts of IIn as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a thirty-first embodiment of the second aspect, compounds haveformula IIn wherein A′ is

In a thirty-second embodiment of the second aspect, compounds haveformula IIo:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIo as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a thirty-third embodiment of the second aspect, compounds haveformula IIo wherein A′ is

In an thirty-fourth embodiment of the second aspect, compounds haveformula IIp:

wherein:

-   -   each X^(b) and X^(c) is independently C or N;    -   X^(b1) is N or O; and    -   X^(b2) is S(O)₂ or C(O).

The compounds of the present invention include pharmaceuticallyacceptable salts of IIp as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a thirty-fifth embodiment of the second aspect, compounds haveformula IIp wherein A′ is

In a thirty-sixth embodiment of the second aspect, compounds haveformula IIq:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIq as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a thirty-seventh embodiment of the second aspect, compounds haveformula IIq wherein A′ is

In a third aspect of the invention, compounds have formula III:

wherein

-   -   A′ is selected from the group consisting of a single bond,

and

-   -   each X^(c) is independently C or N.

The compounds of the present invention include pharmaceuticallyacceptable salts of III as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a first embodiment of the third aspect, compounds have formula IIIwherein A′ is

In a second embodiment of the third aspect, compounds have formula IIIa:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIIa as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a third embodiment of the third aspect, compounds have formula IIIawherein A′ is

In a fourth embodiment of the third aspect, compounds have formula IIIb:

wherein each X^(b) is independently C or N.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIIb as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a fifth embodiment of the third aspect, compounds have formula IIIbwherein A′ is

In a sixth embodiment of the third aspect, compounds have formula IIIc:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIIc as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a seventh embodiment of the third aspect, compounds have formula IIIcwherein A′ is

In an eighth embodiment of the third aspect, compounds have formulaIIId:

The compounds of the present invention include pharmaceuticallyacceptable salts of IIId as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a ninth embodiment of the third aspect, compounds have formula IIIe:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of Me as well as an optically pure enantiomer, racemateor diastereomeric mixtures thereof.

In a tenth embodiment of the third aspect, compounds have formula IIIf:

The compounds of the present invention include pharmaceuticallyacceptable salts of IIIf as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In an eleventh embodiment of the third aspect, compounds have formulaIIIg:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of Mg as well as an optically pure enantiomer, racemateor diastereomeric mixtures thereof.

In a twelfth embodiment of the third aspect, compounds have formulaIIIh:

wherein each X^(b) is independently C or N.

The compounds of the present invention include pharmaceuticallyacceptable salts of Illh as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a thirteenth embodiment of the third aspect, compounds have formulaIIIh wherein A′ is

In a fourteenth embodiment of the third aspect, compounds have formulaIIIi:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIIi as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a fifteenth embodiment of the third aspect, compounds have formulaIIIi wherein A′ is

In a sixteenth embodiment of the third aspect, compounds have formula

The compounds of the present invention include pharmaceuticallyacceptable salts of IIIj as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a seventeenth embodiment of the third aspect, compounds have formulaIIIk:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIIk as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In an eighteenth embodiment of the third aspect, compounds have formulaIIIl:

The compounds of the present invention include pharmaceuticallyacceptable salts of IIIl as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a nineteenth embodiment of the third aspect, compounds have formulaIIIm:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIIm as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a twentieth embodiment of the third aspect, compounds have formulaIIIn:

wherein each X^(b) is independently C or N.

The compounds of the present invention include pharmaceuticallyacceptable salts of Inn as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a twenty-first embodiment of the third aspect, compounds have formulaIIIn wherein A′ is

In a twenty-second embodiment of the third aspect, compounds haveformula IIIo:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIIo as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a twenty-third embodiment of the third aspect, compounds have formulaIIIo wherein A′ is

In a twenty-fourth embodiment of the third aspect, compounds haveformula IIIp:

The compounds of the present invention include pharmaceuticallyacceptable salts of IIIp as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a twenty-fifth embodiment of the third aspect, compounds have formula

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of IIIq as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a fourth aspect of the invention, compounds have formula IV:

wherein:

-   -   A′ is selected from the group consisting of a single bond,

and

-   -   each X^(b) and X^(c) is independently C or N.

The compounds of the present invention include pharmaceuticallyacceptable salts of IV as well as an optically pure enantiomer, racemateor diastereomeric mixtures thereof.

In a first embodiment of the fourth aspect, compounds have formula IVwherein A′ is

In a second embodiment of the fourth aspect, compounds have formula IVa:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of IVa as well as an optically pure enantiomer,racemate or diastereomeric mixtures thereof.

In a third embodiment of the fourth aspect, compounds have formula IVawherein A′ is

In a fifth aspect of the invention, compounds have formula V:

wherein:

-   -   A′ is selected from the group consisting of a single bond,

and

-   -   each X^(c) is independently C or N with the proviso that no more        than two X^(c) are N.

The compounds of the present invention include pharmaceuticallyacceptable salts of V as well as an optically pure enantiomer, racemateor diastereomeric mixtures thereof.

In a first embodiment of the fifth aspect, compounds have formula Vwherein A′ is

In a second embodiment of the fifth aspect, compounds have formula Va:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of Va as well as an optically pure enantiomer, racemateor diastereomeric mixtures thereof.

In a third embodiment of the fifth aspect, compounds have formula Vawherein A′ is

In a fourth embodiment of the fifth aspect, compounds have formula Vb:

wherein each X^(b) is independently C or N.

The compounds of the present invention include pharmaceuticallyacceptable salts of Vb as well as an optically pure enantiomer, racemateor diastereomeric mixtures thereof.

In a fifth embodiment of the fifth aspect, compounds have formula Vbwherein A′ is

In a sixth embodiment of the fifth aspect, compounds have formula Vc:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of Vc as well as an optically pure enantiomer, racemateor diastereomeric mixtures thereof.

In a seventh embodiment of the fifth aspect, compounds have formula Vcwherein A′ is

In an eighth embodiment of the fifth aspect, compounds have formula Vd:

The compounds of the present invention include pharmaceuticallyacceptable salts of Vd as well as an optically pure enantiomer, racemateor diastereomeric mixtures thereof.

In a ninth embodiment of the fifth aspect, compounds have formula Ve:

wherein X and X′ are each independently selected from the groupconsisting of a bond, —CH₂—, —CH₂—CH₂—, —CH═CH—, —O—, —S—, —S(O)₁₋₂—,—CH₂O—, —CH₂S—, —CH₂S(O)₁₋₂— and —CH₂N(R¹)—, wherein R¹ is chosen fromthe group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl,alkoxycarbonyl, carbamoyl and substituted sulfonyl.

The compounds of the present invention include pharmaceuticallyacceptable salts of Ve as well as an optically pure enantiomer, racemateor diastereomeric mixtures thereof.

In a sixth aspect of the invention, in any compound of any of the secondthrough fifth aspects, R^(c), R^(d), R^(e) and R^(f) are eachindependently selected from the group consisting of: hydrogen, C₁ to C₈alkyl and C₁ to C₈ heteroalkyl, wherein,

-   -   each hetero atom, if present, is independently N, O or S,    -   R^(c) and R^(d) are optionally joined to form a 4- to 8-membered        heterocycle which is optionally fused to another 3- to        6-membered heterocycle, and    -   R^(e) and R^(f) are optionally joined to form a 4- to 8-membered        heterocycle which is optionally fused to another 3- to        6-membered heterocycle.

In a first embodiment of the sixth aspect, R^(c) and R^(d) or R^(e) andR^(f) are joined to form a 4- to 8-membered heterocycle which isoptionally fused to another 3- to 6-membered heterocycle.

In a second embodiment of the sixth aspect, both of R^(c) and R^(d) andR^(e) and R^(f) are joined to form a 4- to 8-membered heterocycle whichis optionally fused to another 3- to 6-membered heterocycle.

In a seventh aspect of the invention, each R^(a), if present in any ofthe other aspects of the invention, is independently —CN, —OCHF₂, —OCF₃,—CF₃, or —F.

In an eighth aspect of the invention, if present in any compound of anyof the other aspects, one of Y and Y′ is N.

In a first embodiment of the eighth aspect, both Y and Y′ are N.

In a ninth aspect of the invention, Z and Z′ in any of the previousaspects are each 1-3 amino acids.

In a first embodiment of the ninth aspect, the amino acids are in the Dconfiguration.

In a tenth aspect of the invention, Z and Z′ in any of the previousaspects are each independently selected from the group consisting of—[U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸,—U—(CR⁴ ₂)_(t)—R⁸ and —[U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)]_(u)—U—(CR⁴₂)_(t)—O—(CR⁴ ₂)_(t)—R⁸.

In a first embodiment of the tenth aspect, both of Z and Z′ are —[U—(CR⁴₂)_(t)—NR⁵—(CR⁴ ₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸.

In a second embodiment of the tenth aspect, one or both of Z and Z′ are—U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸.

In a third embodiment of the tenth aspect, one or both of Z and Z′ are—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸.

In a fourth embodiment of the tenth aspect, one or both of Z and Z′ are—[C(O)—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴₂)_(t)—R⁸.

In a fifth embodiment of the tenth aspect, one or both of Z and Z′ are—C(O)—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸.

In a sixth embodiment of the tenth aspect, one or both of Z and Z′ are—[C(O)—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)]_(u)—C(O)—(CR⁴ ₂)_(t)—NR⁷—(CR⁴₂)_(t)—R⁸.

In a seventh embodiment of the tenth aspect, one or both of Z and Z′ are—C(O)—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)—C(O)—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸.

In an eighth embodiment of the tenth aspect, one or both of Z and Z′ are—C(O)—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸.

In a ninth embodiment of the tenth aspect, one or both of Z and Z′ are—C(O)—(CR⁴ ₂)_(n)—NR⁷—(CR⁴ ₂)_(n)—C(O)—R⁸¹.

In a tenth embodiment of the tenth aspect, one or both of Z and Z′ are—C(O)—(CR⁴ ₂)_(n)—NR⁷—C(O)—R⁸¹.

In an eleventh embodiment of the tenth aspect, one or both of Z and Z′are —C(O)—(CR⁴ ₂)_(n)—NR⁷—(CR⁴ ₂)_(n)—C(O)—O—R⁸¹.

In a twelfth embodiment of the tenth aspect, one or both of Z and Z′ are—C(O)—(CR⁴ ₂)_(n)—NR⁷—C(O)—O—R⁸¹.

In a thirteenth embodiment of the tenth aspect, one or both of Z and Z′are —U—(CR⁴ ₂)_(t)—R⁸.

In a fourteenth embodiment of the tenth aspect, one or both of Z and Z′are —C(O)—(CR⁴ ₂)_(t)—R⁸.

In a fifteenth embodiment of the tenth aspect, one or both of Z and Z′are —[U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—O—(CR⁴ ₂)_(t)—R⁸.

In a sixteenth embodiment of the tenth aspect, one or both of Z and Z′are —U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)—U—(CR⁴ ₂)_(t)—O—(CR⁴ ₂)_(t)—R⁸.

In a seventeenth embodiment of the tenth aspect, one or both of Z and Z′are —C(O)—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)—C(O)—(CR⁴ ₂)_(t)—O—(CR⁴ ₂)_(t)—R⁸.

In an eighteenth embodiment of the tenth aspect, one or both of Z and Z′are —U—(CR⁴ ₂)_(t)—O—(CR⁴ ₂)_(t)—R⁸.

General Synthesis

The following schemes exemplify some of the synthetic routes that areused for the preparations of compounds and their analogs included inthis invention. These skilled in the art will understand thatalternative routes may also be used to reach the same and similarlyfunctionalized intermediates and target molecules. Alternative reagentsfor a given transformation are also possible.

The following abbreviations are used throughout this application:

-   -   ACN Acetonitrile    -   aq Aqueous    -   Bn Benzyl    -   BnOH Benzyl alcohol    -   Boc t-butoxycarbonyl    -   DCE Dichloroethane    -   DCM Dichloromethane    -   DIEA(DIPEA) Diisopropylethylamine    -   DMA N,N-Dimethylacetamide    -   DME 1,2-Dimethoxyethane    -   DMF N,N-Dimethylformamide    -   DMSO Dimethylsulfoxidc    -   DMTMM 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium        chloride    -   DPPA Diphenylphosphoryl azide    -   DTT Dithiothreitol    -   EDC Ethylcarbodiimide hydrochloride    -   EDCl 1-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide        hydrochloride    -   EDTA Ethylene diamine tetraacetic acid    -   ESI Electrospray Ionization    -   Et₃N, TEA Triethylamine    -   EtOAc, EtAc Ethyl acetate    -   EtOH Ethanol    -   g Gram(s)    -   h Hour(s)    -   HBTU O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   HOBt 1-Hydroxybenzotriazole    -   IC₅₀ The concentration of an inhibitor that causes a 50%        reduction in a measured activity    -   LAH Lithium aluminum hydride    -   LDA Lithium diisopropylamide    -   LCMS Liquid Chramatography Mass Spectrometry    -   MeI Methyl Iodide    -   MeOH Methanol    -   min Minute(s)    -   mmol Millimole(s)    -   NMM 4-Methylmorpholine    -   NMP N-methylpyrrolidinone    -   PG Protective Group    -   PTT Phenyl trimethyl tribromide    -   Py Pyridine    -   rt Room temperature    -   TEA Triethylamine    -   Tf Trifluoromethanesulfonate    -   TFA Trifluoroacetic acid    -   TFAA Trifluoroacetic anhydride    -   THF Tetrahydrofuran    -   TLC Thin Layer Chromatography

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). 1H-NMR spectra wererecorded on a Brukcr 400 MHz or 500 MHz NMR spectrometer. Significantpeaks are tabulated in the order: multiplicity (s, singlet; d, doublet;t, triplet; q, quartet; m, multiplet; br s, broad singlet), couplingconstant(s) in Hertz (Hz) and number of protons. Electrospray sprayionization (ESI) mass spectrometry analysis was conducted on aHewlett-Packard 1100 MSD electrospray mass spectrometer using the HP1100 HPLC for sample delivery. Mass spectrometry results are reported asthe ratio of mass over charge, followed by the relative abundance ofeach ion (in parentheses) or a single m/z value for the M+H (or, asnoted, M−H) ion containing the most common atomic isotopes. Isotopepatterns correspond to the expected formula in all cases. Normally theanalyte was dissolved in methanol at 0.1 mg/mL and 5 microliter wasinfused with the delivery solvent into the mass spectrometer, whichscanned from 100 to 1500 daltons. All compounds could be analyzed in thepositive ESI mode, using an acetonitrile/H₂O gradient (10%-90%)acetonitrile in H₂O with 0.1% formic acid as delivery solvent. Thecompounds provided below could also be analyzed in the negative ESImode, using 2 mM NH₄OAc in acetonitrile/H₂O as delivery solvent.Enantiomeric purity was determined using a Hewlett-Packard Series 1050system equipped with a chiral HLPC column (ChiralPak AD, 4.6 mm×150 mm)and isocratic elution using 5:95 isopropanol-hexane as a mobile phase.

The compounds were named using ChemDraw program from Cambridge Soft Inc.

Example 1 Synthesis of compounds of Formula IIc

Scheme 1-1 describes preparation of target molecules and their analogswith symmetrical and non-symmetrical functionalized ends.

Step a.

To a solution of 2-bromonaphthane a (62.0 g, 300 mmol) in DCM (1 L) wasadded AlCl₃ (44.0 g, 330 mmol) and 2-chloroacetyl chloride (34.0 g, 330mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h andthen H₂O added (500 mL) and extracted. The organic layer was washed withH₂O, dried over anhydrous Na₂SO₄, evaporated under reduced pressure togive 80 g crude product, which was purified by re-crystallization from10% EtOAc-hexane (v/v) to yield b (28 g, 36% yield) as a white solid: ¹HNMR (500 MHz, CDCl₃) δ 8.44 (s, 1H), 8.07 (s, 1H), 8.04 (d, J=11.0 Hz,1H), 7.84 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.5 Hz, 1H), 4.81 (s, 2H) ppm;LCMS (ESI) m/z 282.9 (M+H)⁺.

Step b.

To a solution of b (28.0 g, 100 mmol) in DCM (500 mL) was addedN-Boc-L-Pro-OH (24.7 g, 115 mmol) and Et₃N (70.0 mL, 500 mmol) and themixture was stirred at rt for 2 h. The mixture was concentrated underreduced pressure to afford crude c which was used for the next stepwithout further purification. LC-MS (ESI) m/z 462.1 (M+H)⁺.

Step c.

To a solution of c (46.0 g, 100 mmol) in toluene (500 mL) was addedNH₄OAc (77 g, 1.0 mol) and the mixture was stirred at 110° C. overnight,and concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (petroleum ether/EtOAc 1:1(v/v)) to afford d (30 g, 68% yield) as a yellow solid: LC-MS (ESI) m/z442.1 (M+H)⁺.

Step d.

To a solution of d (10.0 g, 23.0 mmol) in anhydrous DME (200 mL) andequal molar of boronate e was added PPh₃ (1.2 g, 4.6 mmol), Pd(PPh₃)₄(1.6 g, 2.3 mmol), and 2.0 M Na₂CO₃ solution. The mixture was refluxedunder argon overnight. The organic solvent was removed under reducedpressure and the residue was treated with H₂O, extracted with EtOAc(2×200 mL). The combined organic phase was dried, filtered, andconcentrated in vacuo to give a residue, which was purified by silicagel column chromatography (petroleum ether/EtOAc 3:1 (v/v)) to afford f(10 g, 96% yield) as a yellow solid. LC-MS (ESI): m/z 709.3 (M+H)⁺.

Step e.

To a stirred solution of f (150 mg, 0.29 mmol) in dioxane (3 mL) wasadded 4.0 N HCl in dioxane (3 mL) dropwise. The mixture was stirred atrt for 4 h, and then concentrated to yield a yellowish solid (134 mg),which was used directly for the next step. The residue (134 mg, 0.290mmol) was suspended in THF (5 mL) and DIPEA (0.32 mL) was added andfollowed by addition of N-methoxycarbonyl-L-Val-OH (151 mg, 0.860 mmol).After stirring for 15 min, HATU (328 mg, 0.860 mmol) was added and themixture was stirred at rt for another 2 h and then concentrated. Theresidue was purified by prep-HPLC to obtain g (40 mg, 19% yield).

Step a.

Referring to Scheme 1-2, to a solution of compound 3 (2.0 g, 4.5 mmol)in dioxane (25 mL) was added 4.0 N HCl in dioxane (25 mL). Afterstirring at rt for 4 h, the reaction mixture was concentrated and theresidue was dried in vacuo to give a yellowish solid (2.1 g), which wasused directly for the next step without further purification.

Step b.

To the residue of step a (4.5 mmol) was added DMF (25 mL), followed byadding DIPEA (3.7 mL, 22.5 mmol) and N-methyl carbamate-L-valine (945mg, 5.4 mmol). After stirring at rt for 15 min, the reaction mixture wasadded slowly to H₂O (400 mL). A white solid precipitated was filteredand dried to give compound 6 (2.2 g, 98% yield). LC-MS (ESI): m/z 499.1(M+H)⁺.

Step c.

To a mixture of compound 6 (800 mg, 1.6 mmol), compound 7 (718 mg, 1.6mmol), and NaHCO₃ (480 mg, 5.7 mmol) in 1,2-dimethoxyethane (15 mL) andH₂O (5 mL) was added Pd(dppf)Cl₂ (59 mg, 0.08 mmol). After stirring at80° C. overnight under an atmosphere of N₂, the reaction mixture wasconcentrated. The residue was partitioned between 20% methanol/CHCl₃(100 mL) and H₂O (100 mL). The organic phase was separated and theaqueous phase was extracted with 20% methanol/CHCl₃ (100 mL) again. Thecombined organic phase was consequently washed with brine, dried withanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedby silica gel column chromatography (Petroleum ether/EtOAc=15:1 (v/v))to give compound 8 (1.0 g, 85% yield) as a yellow solid. LC-MS (ESI):m/z 732.4 (M+H)⁺.

Step d.

To a solution of compound 8 (200 mg, 0.27 mmol) in dioxane (3.0 mL) wasadded 4 N HCl in dioxane (3.0 mL). After stirring at rt for 2 h, thereaction mixture was concentrated and the residue was dried in vacuo togive an HCl salt in quantitative yield, which was used directly for thenext step without further purification.

Step e.

To a solution of the salt (0.27 mmol) in DMF (5.0 mL) was added DIPEA(0.47 mL, 2.7 mmol), followed by adding N,N-dimethyl-D-phenyl glycine(59 mg, 0.33 mmol) and HATU (125 mg, 0.33 mmol). After stirring at rtfor 1 h, the reaction mixture was partitioned between H₂O and DCM. Theorganic phase was washed successively with H₂O and brine, dried withanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedby prep-HPLC to give compound 9. LC-MS (ESI): m/z 793.4 (M+H)⁺.

Step a.

To a mixture of compound 3 (3.2 g, 7.2 mmol), bis(pinacolato)diboron(3.86 g, 15.2 mmol), and KOAc (1.85 g, 18.8 mmol) in 1,4-dioxane (100mL) was added Pd(dppf)Cl₂ (440 mg, 0.6 mmol). After stirring at 80° C.for 3 h under an atmosphere of N₂, the reaction mixture wasconcentrated. The residue was purified with silica gel columnchromatography (Petroleum ether/EtOAc=2/1 (v/v)) to give compound 11(2.8 g, 80% yield) as a white solid. LC-MS (ESI): m/z 490.3 (M+H)^(|).

Step b.

To a mixture of compound 11 (626 mg, 1.27 mmol), compound 12 (570 mg,1.27 mmol), and NaHCO₃ (420 mg, 4.99 mmol) in 1,2-dimethoxyethane (30mL) and H₂O (10 mL) was added Pd(dppf)Cl₂ (139 mg, 0.19 mmol). Afterstirring at 80° C. overnight under an atmosphere of N₂, the reactionmixture was concentrated. The residue was partitioned between 20%methanol/CHCl₃ (100 mL) and H₂O (100 mL). The aqueous phase wasextracted with 20% methanol/CHCl₃ (100 mL) again. The combined organicphase was consequently washed with brine, dried with anhydrous Na₂SO₄,filtered, and concentrated. The residue was purified by silica gelcolumn chromatography (Petroleum ether/EtOAc=2/1 (v/v)) to give compound13 (635 mg, 68% yield) as a yellow solid. LC-MS (ESI): m/z 732.4 (M+H)⁺.

Step c.

To a solution of compound 13 (200 mg, 0.27 mmol) in dioxane (3.0 mL) wasadded 4 N HCl in dioxane (3.0 mL). After stirring at rt for 2 h, thereaction mixture was concentrated and the residue was dried in vacuo toyield the HCl salt of compound 14 in quantitative yield, which was useddirectly for the next step without further purification.

Step d.

To a solution of the salt (0.27 mmol) in DMF (5.0 mL) was added DIPEA(0.47 mL, 2.7 mmol), followed by adding N,N-dimethyl-D-phenyl glycine(59 mg, 0.33 mmol) and HATU (125 mg, 0.33 mmol). After stirring at rtfor 1 h, the reaction mixture was partitioned between H₂O and DCM. Theorganic phase was consequently washed with H₂O and brine, dried withanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedby prep-HPLC to give compound 15. LC-MS (ESI): m/z 793.4 (M+H)⁺.

Example 2 Synthesis of compounds of Formula IIIe

Step a.

Referring to Scheme 2-1, to a mixture of compound 1 (5.05 g, 13.8 mmol),bis(pinacolato)diboron (7.1 g, 27.9 mmol), and KOAc (3.2 g, 32.5 mmol)in 1,4-dioxane (100 mL) was added Pd(dppf)Cl₂ (400 mg, 0.5 mmol). Afterstirring at 80° C. for 3 h under an atmosphere of N₂, the reactionmixture was concentrated. The residue was purified by silica gel columnchromatography (Petroleum ether/EtOAc=2/1 (v/v)) to give compound 2 (3.0g, 53% yield) as a gray solid. LC-MS (ESI): m/z 414.2 (M+H)^(|).

Step b.

To a mixture of compound 2 (522 mg, 1.26 mmol), compound 3 (500 mg, 1.13mmol), and NaHCO₃ (333 mg, 3.96 mmol) in 1,2-dimethoxyethane (30 mL) andH₂O (10 mL) was added Pd(dppf)Cl₂ (74 mg, 0.1 mmol). After stirring at80° C. overnight under an atmosphere of N₂, the reaction mixture wasconcentrated. The residue was partitioned between 20% methanol/CHCl₃(100 mL) and H₂O (100 mL). The organic phase was separated and theaqueous phase was extracted with 20% methanol/CHCl₃ (100 mL) again. Thecombined organic phase was consequently washed with brine, dried withanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedby silica gel column chromatography (DCM/MeOH=50:1 (v/v)) to givecompound 4 (450 mg, 55% yield) as a yellow solid. LC-MS (ESI): m/z 649.3(M+H)⁺.

Step c.

To a stirred solution of compound 4 (160 mg, 0.25 mmol) in dioxane (2.0mL) was added 4N HCl in dioxane (2.0 mL). After stirring at rt for 3 h,the reaction mixture was concentrated and the residue was dried in vacuoto give an HCl salt in quantitative yield, which was used directly forthe next step without further purification.

Step d.

To a solution of above salt (0.25 mmol) in DMF (4.0 mL) was added DIPEA(0.44 mL, 2.5 mmol), followed by adding N-methyl carbamate-L-Threonine(110 mg, 0.62 mmol) and HATU (240 mg, 0.63 mmol). After stirring at rtfor 1 h, the reaction mixture was partitioned between H₂O and DCM. Theorganic phase was consequently washed with H₂O and brine, dried withanhydrous Na₂SO₄, filtrated, and concentrated. The residue was purifiedby prep-HPLC to give compound 5 as a white powder. LC-MS (ESI): m/z767.3 (M+H)⁺.

Scheme 2-1-1 provides an alternative synthetic pathway to the compoundsdisclosed herein.

Step a.

Referring to Scheme 2-2, to a mixture of compound 2 (1.16 g, 2.32 mmol),compound 6 (1.40 g, 3.39 mmol), and NaHCO₃ (823 mg, 9.8 mmol) in1,2-dimethoxyethane (30 mL) and H₂O (10 mL) was added Pd(dppf)Cl₂ (103mg, 0.14 mmol). After stirring at 80° C. over night under an atmosphereof N₂, the reaction mixture was concentrated. The residue waspartitioned between 20% methanol/CHCl₃ (150 mL) and H₂O (150 mL). Theaqueous phase was extracted with 20% methanol/CHCl₃ (150 mL) again. Thecombined organic phase was consequently washed with brine, dried withanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedby silica gel column chromatography (Petroleum ether/acetone=1.5/1(v/v)) to give compound 16 (1.32 g, 80% yield) as a yellow solid. LC-MS(ESI): m/z 706.4 (M+H)⁺.

Step b.

To a solution of compound 16 (200 mg, 0.28 mmol) in dioxane (3.0 mL) wasadded 4 N HCl in dioxane (3.0 mL). After stirring at rt for 2 h, thereaction mixture was concentrated and the residue was dried in vacuo togive the HCl salt of compound 17 in quantitative yield, which was useddirectly for the next step.

Step c.

To a solution of the salt (0.28 mmol) in DMF (5.0 mL) was added DIPEA(0.49 mL, 2.8 mmol), followed by adding N,N-dimethyl-D-phenyl glycine(61 mg, 0.34 mmol) and HATU (129 mg, 0.34 mmol). After stirring for 1 hat rt, the reaction mixture was partitioned between H₂O and DCM. Theorganic phase was consequently washed with H₂O and brine, dried withanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedby prep-HPLC to give compound 18. LC-MS (ESI): m/z 767.4 (M+H)⁺.

Step a.

Referring to Scheme 2-3, to a solution of compound 1 (4.0 g, 10.9 mmol)in dioxane (40 mL) was added 4 N HCl in dioxane (40 mL). After stirringat rt overnight, the reaction mixture was concentrated. The residue waswashed with DCM, filtered, and dried in vacuo to afford a hydrochloridesalt in quantitative yield, which was used for the next step withoutfurther purification.

Step b.

To a solution of the salt (10.9 mmol) in DMF (30 mL) was added DIPEA(5.8 mL, 33.0 mmol), followed by adding N-methoxycarbonyl-L-valine (2.1g, 12.1 mmol) and HATU (4.6 g, 12.1 mmol). After stirring at rt for 1 h,the reaction mixture was partitioned between H₂O and DCM. The organicphase was consequently washed with H₂O and brine, dried with anhydrousNa₂SO₄, filtered, and concentrated. The residue was purified by silicagel column chromatography (DCM/Petroleum ether=4/1 (v/v)) to givecompound 19 (3.0 g, 65% yield). LC-MS (ESI): m/z 423.1 (M+H)⁺.

Step c.

To a mixture of compound 11 (800 mg, 1.9 mmol), compound 19 (700 mg, 1.7mmol), and NaHCO₃ (561 mg, 6.6 mmol) in 1,2-dimethoxyethane (60 mL) andH₂O (20 mL) was added Pd(dppf)Cl₂ (183 mg, 0.25 mmol). After stirring at80° C. overnight under an atmosphere of N₂, the reaction mixture wasconcentrated. The residue was then partitioned between 20%mcthanol/CHCl₃ (100 mL) and H₂O (100 mL). The aqueous phase wasextracted with 20% methanol/CHCl₃ (100 mL) again. The combined organicphase was consequently washed with brine, dried with Na₂SO₄, filtered,and concentrated. The residue was purified by silica gel columnchromatography (Petroleum ether/EtOAc=2/1 (v/v)) to give compound 20(600 mg, 52% yield) as a yellow solid. LC-MS (ESI): m/z 706.4 (M+H)⁺.

Step d.

To a solution of compound 20 (200 mg, 0.28 mmol) in dioxane (3.0 mL) wasadded 4N HCl in dioxane (3.0 mL). After stirring at rt for 2 h, thereaction mixture was concentrated and the residue was dried in vacuo toyield the HCl salt of compound 21 in quantitative yield, which was useddirectly for the next step without further purification.

Step e.

To a solution of compound 21 (0.28 mmol) in DMF (5.0 mL) was added DIPEA(0.49 mL, 2.8 mmol), followed by N,N-dimethyl-D-phenyl glycine (64 mg,0.36 mmol) and HATU (129 mg, 0.34 mmol). After stirring at rt for 1 h,the reaction mixture was partitioned between H₂O and DCM. The organicphase was washed successively with H₂O and brine, dried with anhydrousNa₂SO₄, filtered, and concentrated. The residue was purified byprep-HPLC to give compound 22. LC-MS (ESI): m/z 767.4 (M+H)⁻.

Step a.

To a mixture of compound 74 (510 mg, 1.09 mmol), compound 138 (300 mg,0.68 mmol), NaHCO₃ (228 mg, 2.72 mmol) in 1,2-dimethoxyethane (20 mL)and H₂O (5 mL) was added Pd(dppf)Cl₂.CH₂Cl₂ (111 mg, 0.140 mmol) at rtunder an atmosphere of N₂. After stirring at 80° C. overnight under anatmosphere of N₂, the reaction mixture was concentrated and the residuewas diluted with EtOAc (100 mL) and H₂O (25 mL). The organic phase waswashed with brine and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(Petroleum ether/EtOAc=1/2 (v/v)) to give compound 142 (360 mg, 75%yield) as a yellow solid. LC-MS (ESI): m/z 707.4 (M+H)⁺.

Step b.

To a solution of compound 142 (115 mg, 0.16 mmol) in dioxane (2.0 mL)was added 4 N HCl in dioxane (2.0 mL) at rt. After stirring at rtovernight, the reaction mixture was concentrated and the residue wasdried in vacuo to give an HCl salt, which was used for the next stepwithout further purification. LC-MS (ESI) m/z 607.3 (M+H)⁺.

Step c.

Subsequently, the HCl salt was dissolved in DMF (2 mL) and the resultingmixture was added DIEA (0.28 mL, 1.6 mmol),N-Moc-L-(tetrahydro-2H-pyran-4-yl)glycine (41 mg, 0.19 mmol), and HATU(73 mg, 0.19 mmol). After stirring at rt for 15 min, the reactionmixture was concentrated and the residue was purified by preparativeHPLC to give compound 143. LC-MS: (ESI) m/z 806.4 (M+H)⁺.

Example 3 Synthesis of Additional Compounds of Formula IIc

Step a.

Referring to Scheme 3-1, to a solution of compound 1 (49.7 g, 0.25 mol)in DMSO was added 40% aq. HBr (0.50 mol) drop wise at rt. After stirringat 90° C. for 3 h, the reaction mixture was poured into H₂Oand theresulting mixture was kept at 50˜60° C. The yellow solid was collectedby filtration and re-crystallized in acetone/H₂O (1/19 (v/v) two timesto give compound 2 (50 g, 87% yield). LC-MS (ESI): m/z 212.9 (M+H)⁺.

Step b.

A mixture of 2 (19.0 g, 80.0 mmol) and 4-bromobenzene-1,2-diamine (15.0g, 80.0 mmol) in HOAc (180 mL) was refluxed overnight. Subsequently, thereaction mixture was poured into ice H₂O. The solid was collected byfiltration and purified by silica gel column chromatography to givecompounds 3 and 3′ (2.8 g, 10% yield) as a pair of regioisomers. LC-MS(ESI): m/z 362.9 (M+H)⁺.

Step c.

A mixture of compound 3 (4.8 g, 5.4 mmol), bis(pinacolato)diboron (9.6g, 38 mmol), potassium acetate (3.8 g, 38 mmol), and Pd(dppf)Cl₂.CH₂Cl₂(524 mg, 0.54 mmol) in dioxane (100 mL) was stirred at 80° C. for 17 hunder an atmosphere of Ar. Subsequently, the reaction mixture wasfiltered. The filtered cake was washed with EtOAc (50 mL×3) severaltimes. The filtrate was washed with H₂O and dried with anhydrous Na₂SO₄.The solvent was removed and the residue was purified by silica gelcolumn chromatography (PE/acetone=10:1 (v/v)) to give compounds 4 and 4′(2.2 g, 89% yield) as a pair of regio-isomers. LC-MS (ESI): m/z 459.3(M+H)⁺. (The corresponding boronic acid was also isolated and used as anactive intermediate for the next step).

Step d.

A mixture of compounds 4 and 4′ (1.0 g, 2.2 mmol), (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (2.0 g, 5.4 mmol),sodium bicarbonate (1.5 g, 18 mmol), and Pd(dppf)Cl₂.CH₂Cl₂ (427 mg,0.44 mmol) in DME/H₂O (3/1 (v/v) (80 mL) was stirred at 80° C. for 17 hunder an atmosphere of Ar. Subsequently, the reaction mixture wasconcentrated and the residue was diluted with EtOAc (100 mL). Theorganic layer was washed with brine and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (PE/acetone=10:1 (v/v)) to give compounds 5 and 5′ (590mg, 40% yield) as a pair of regio-isomers. LC-MS (ESI): m/z 677.3(M+H)⁺.

Step e.

A mixture of compounds 5 and 5′ (200 mg, 0.3 mmol) in 4.0 N HCl indioxane (10 mL) was stirred at rt overnight. The solvent was removed andthe residue was dried in vacuo to give an HCl salt, which was used forthe next step without further purification. LC-MS (ESI): m/z 477.2(M+H)⁺.

Step f.

Subsequently, the HCl salt was dissolved in DMF (3 mL) and the resultingmixture was sequentially added Et₃N (304 mg, 3.0 mmol), N-Moc-L-Val-OH(116 mg, 0.66 mmol) and HATU (251 mg, 0.66 mmol). After stirring at rtfor 2 h, the reaction mixture was poured into H₂O (50 mL) and theresulting suspension was extracted with DCM several times (20 mL×3). Theextracts were combined, washed with brine, and dried with anhydrousMgSO₄. The solvent was removed and the residue was purified bypreparative HPLC and to give compounds 6 and 6′ as a pair ofregio-isomers. LC-MS (ESI): m/z 791.4 (M+H)⁺.

Step a.

Referring to Scheme 3-2, to a solution of compound 7 (909 mg, 1.86mmol),(S)-tert-butyl-2-(5-(6-bromopyridin-3-yl)pyrrolidine-1-carboxylate (800mg, 2.04 mmol), and NaHCO₃ (625 mg, 7.44 mmol) in 1,2-dimethoxyethane(100 mL) and H₂O (30 mL) was added Pd(dppf)Cl₂ (152 mg, 0.186 mmol) atrt under an atmosphere of Ar. After stirring at 80° C. overnight underan atmosphere of Ar, the reaction mixture was concentrated. The residuewas diluted with CH₂Cl₂ (200 mL). The organic layer was washed with H₂Oand dried with anhydrous Na₂SO₄. The solvent was removed and the residuewas purified by silica gel column chromatography (DCM/MeOH=50:1 (v/v))to give compound 8 (700 mg, 55% yield). LC-MS (ESI) m/z: 676.4 (M+H)⁺.

Step b.

To a stirred solution of compound 8 (200 mg, 0.296 mmol) in dioxane (3mL) was added 4 N HCl in dioxane (3 mL). After stirring at rt for 4 h,the reaction mixture was concentrated and the residue was dried in vacuoto give an HCl salt, which was used for the next step without furtherpurification. LC-MS (ESI) m/z: 476.2 (M+H)⁺.

Step c.

Subsequently, the HCl salt was dissolved in DMF (3 mL) and the resultingmixture was sequentially added DIEA (388 mg, 3.0 mmol), N-Moc-L-Val-OH(116 mg, 0.66 mmol) and HATU (251 mg, 0.66 mmol). After stirring at rtfor 2 h, the reaction mixture was poured into H₂O (50 mL) and theresulting suspension was extracted with DCM several times (20 mL×3). Theextracts were combined, washed with brine, and dried with anhydrousMgSO₄. The solvent was removed and the residue was purified bypreparative HPLC and to give compound 9. ¹H NMR (500 MHz, CDCl₃) δ 9.09(s, 1H), 8.67 (s, 1H), 8.31-8.34 (m, 3H), 8.27-8.29 (m, 1H), 8.17-8.19(m, 1H), 8.11-8.13 (m, 1H), 8.07 (s, 1H), 8.04 (s, 1H), 7.90-7.91 (m,1H), 5.29-5.31 (m, 2H), 4.26-4.27 (m, 2H), 4.13 (s, 2H), 3.93-3.95 (m,2H), 3.68 (s, 6H), 2.60-2.62 (m, 3H), 2.32-2.33 (m, 2H), 2.15-2.28 (m,5H), 2.10-2.11 (m, 3H), 1.00-1.02 (m, 2H), 0.96-0.98 (m, 6H), 0.92-0.93(m, 6H) ppm. LC-MS (ESI): m/z 790.4 (M+H)⁻.

Step a.

Referring to Scheme 3-3, to a solution of 10 (45.0 g, 247 mmol) in MeOH(500 mL) was added NaOMe (1.4 g, 25 mmol) at rt. After stirring at rtfor 48 h, the reaction mixture was added NH₄CL (13.4 g, 250 mmol) andthe resulting mixture was stirred from another 24 h. The solvent wasremoved and the residue was dried in vacuo to give compound 11, whichwas used for the next step without further purification. LC-MS: (ESI)m/z=199.0 (M+H)^(|).

Step b.

To a solution of 11 (15 g, 75 mmol) in CH₃CN (500 mL) was added K₂CO₃(11.4 g, 83.0 mmol), followed by 2-fluoro-5-nitrobenzaldehyde (12.7 g,75.0 mmol). After refluxing for 12 h, the reaction mixture wasconcentrated and the residue was washed with MeOH to give crude compound12 (12 g), which was used for the next step without furtherpurification. LC-MS: (ESI) m/z=330.0 (M+H)^(|).

Step c.

A solution of 12 (5.0 g, 15 mmol) in MeOH (500 mL) was added tin (II)chloride (14.3 g, 75.0 mmol) and concentrated hydrochloric acid (17 mL).After stirring at rt for 3.5 h, the reaction mixture was carefully addedsaturated aqueous NaHCO₃ solution (470 mL). The resulting mixture wasextracted with ethyl acetate (100 mL×3). The extracts were combined andwashed with brine and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was dried in vacuo to give crude compound 13(2.5 g). LC-MS: (ESI) m/z=300.0 (M+H)⁺.

Step d.

To a solution of 13 (300 mg, 1.0 mmol) in concentrated HCl (0.25 mL) wasadded a solution of NaNO₂ (76 mg, 1.1 mmol) in H₂O (1 mL) drop wise at0° C. After stirring at 0° C. for 30 min, the reaction mixture was addedto a solution of K₂CO₃ (207 mg, 1.5 mmol) and Et₂NH (0.11 g, 1.5 mmol)in ice H₂O (1 mL). Subsequently, ether (100 mL) was added to themixture. The organic layer was separated, washed with H₂O (15 mL) anddried with anhydrous Na₂SO₄. The solvent was removed and the residue wasdried in vacuo to give crude compound 14 (350 mg), which was used forthe next step without further purification. LC-MS (ESI): m/z 384.1(M+H)⁺.

Step e.

To a solution of compound 14 (1.8 g, 4.7 mmol) and LiBr (834 mg, 9.6mmol) in acetonitrile (10 mL) was added TMSCl (782 mg, 7.2 mmol) at rt.After stirring at 60° C. for 15 min, the reaction mixture was cooled tort and treated with 5% aqueous NaHCO₃ solution (30 mL). The mixture wasconcentrated and the residue was extracted with CH₂Cl₂ (50 mL×3). Theextracts were combined, washed with brine, and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was purified by silicagel column chromatography (Pentane/ether=1/19 (v/v)) to give compound 15(1.0 g, 59% yield). LC-MS: (ESI) m/z=362.9 (M+H)⁺.

Step f.

To a solution of 15 (300 mg, 0.82 mmol) in dioxane (20 mL) wassequentially added bis(pinacolato)diboron (915 mg, 3.63 mmol), potassiumacetate (403 mg, 4.12 mmol), and Pd(dppf)Cl₂ (134 mg, 0.160 mmol) at rtunder an atmosphere of Ar. After stirring at 80° C. for 17 h under anatmosphere of Ar, the reaction mixture was diluted with EtOAc (100 mL).The resulting mixture was washed with H₂Oand dried with anhydrousNa₂SO₄. The solvent was removed and the residue was purified by silicagel column chromatography (PE/acetone=3/1 (v/v)) to give compound 16(227 mg, 60% yield) LC-MS (ESI): m/z 459.3 (M+H)⁺. (The correspondingboronic acid was also isolated and used as an active intermediate forthe next step).

Step g.

A solution of 16 (300 mg, 0.65 mmol) in DME/H₂O (3/1 (v/v); 30 mL) wassequentially added (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (595 mg, 1.64mmol), NaHCO₃ (443 mg, 5.28 mmol), and Pd(dppf)Cl₂.CH₂Cl₂ (126 mg, 0.13mmol) at rt under an atmosphere of Ar. After stirring at 80° C. for 17 hunder an atmosphere of Ar, the reaction mixture was diluted with EtOAc(150 mL). The organic layer was isolated, washed with brine, and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (PE/acetone=2/1 (v/v)) togive compound 17 (151 mg, 34% yield) as a yellowish solid. LC-MS (ESI):m/z 677.3 (M+H)⁺.

Step h.

To a solution of compound 17 (100 mg, 0.15 mmol) in dioxane (2 mL) wasadded 4 N HCl in dioxane (2 mL) at rt. After stirring at rt overnight,the solvent was removed and the residue was dried in vacuo to give anHCl salt, which was used for the next step without further purification.LC-MS (ESI): m/z 477.2 (M+H)⁺.

Step i.

To a solution of the HCl salt in DMF (2 mL) was added DTPEA (0.24 mL,1.5 mmol), followed by N-Moc-L-Val-OH (65 mg, 0.37 mmol), and HATU (141mg, 0.37 mmol). After stirring at rt for 30 min, the reaction solutionwas poured into H₂O (50 mL). The suspension was filtered and the solidwas purified by preparative HPLC to give compound 18. ¹H NMR (500 MHz,CD₃OD) δ 9.69 (s, 1H), 8.80 (d, 2H, J=7.5), 8.49 (s, 1H), 8.35 (d, 2H,J=8.0), 8.24 (d, 2H, J=8.5), 8.15 (s, 1H), 8.12 (s, 1H), 8.01 (s, 2H),7.93 (d, 2H, J=8.5), 5.30-5.26 (m, 2H), 4.25 (d, 2H, J=6.5), 4.12 (s,2H), 3.91 (s, 2H), 3.67 (s, 6H), 2.61-2.60 (m, 2H), 2.31-2.17 (m, 6H),2.08-2.05 (m, 2H), 1.02-0.91 (m, 12H) ppm; LC-MS (ESI) m/z: 791.4(M+H)^(|).

Step a.

Referring to Scheme 3-4, a solution of 19 (5.00 g, 19.8 mmol) in CH₃CN(200 mL) was respectively added EDCI (9.10 g, 47.6 mmol), HOBt (1.34 g,5.95 mmol), MeNH(OMe).HCl (2.93 g, 30 mmol), and Et₃N (6.6 g, 65.3 mmol)at rt. After stirring at rt for 3 h, the reaction mixture wasconcentrated and the residue was purified by silica gel columnchromatography (Petroleum ether/EtOAc=5/1 (v/v)) to give compound 20(5.1 g, 87% yield) as a white solid. LC-MS (ESI): Fez 295.0 (M+H)⁺.

Step b.

To a solution of compound 20 (2.0 g, 6.8 mmol) in THF (200 mL) wasslowly added 3M MeMgCl in THF (4.5 mL) at 0° C. under an atmosphere ofN₂. After stirring at 0° C. for 1 h and then at rt for 1 h, the reactionwas quenched by adding several drops of aqueous NH₄Cl. The reactionmixture was concentrated and the residue was diluted with aqueous NaHCO₃(5 mL) and EtOAc (100 mL). The organic phase was washed with brine anddried with anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleum ether/AcOEt=10:1(v/v)) to give compound 21 (1.0 g, 59%) as a white solid. LC-MS (ESI):m/z 250.0 (M+H)⁺.

Step c.

A solution of compound 21 (500 mg, 2.0 mmol) in HOAc (20 mL) and 48%aqueous HBr (0.5 mL) was slowly added Br₂ (320 mg, 2.0 mmol) in 48%aqueous HBr (0.5 mL) at rt. After stirring at rt for 2 h, the reactionmixture was concentrated and the residue was diluted with H₂O (100 mL).The mixture was extracted with EtOAc (100 mL×3). The extracts werecombined and washed with saturated NaHCO₃ (30 mL×3) and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give crude compound 22 (440 mg) as a white solid, which wasused for the next step without further purification. LC-MS (EST): m/z327.9 (M+H)⁺.

Step d.

A solution of compound 22 (415 mg, 1.26 mmol) in CH₃CN (15 mL) wasrespectively added N-Boc-L-Pro-OH (300 mg, 1.36 mol) and Et₃N (382 mg,3.78 mmol) at rt. After stirring at rt for 2 h, the reaction mixture wasconcentrated and the residue was dried in vacuo to give crude compound23 (580 mg), which was used for the next step without furtherpurification; LC-MS (ESI): m/z 463.1 (M+H)⁺.

Step e.

A mixture of compound 23 (580 mg, 1.25 mmol) and NH₄OAc (962 mg, 12.5mmol) in toluene (25 mL) was stirred at 110° C. overnight. The reactionmixture was concentrated and the residue was purified by silica gelcolumn chromatography (Petroleum ether/EtOAc=9/1 (v/v)) to give compound24 (400 mg, 72%) as a white solid. LC-MS (EST): m/z 443.1 (M+H)⁺.

Step f.

To a mixture of compound 24 (380 mg, 0.86 mmol), (S)-tert-butyl2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(378 mg, 0.860 mmol), and NaHCO₃ (253 mg, 3.01 mmol) in1,2-dimethoxyethane (15 mL) and H₂O (5 mL) was added Pd(dppf)Cl₂ (35 mg,0.04 mmol) under an atmosphere of N₂. After stirring at 80° C. overnightunder an atmosphere of N₂, the reaction mixture was concentrated. Theresidue was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL×3).The extracts were combined and washed with brine and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was purifiedby silica gel column chromatography (Petroleum ether /EtOAc=5/2 (v/v))to give compound 25 (550 mg, 95% yield) as a yellow solid. LC-MS (ESI):m/z 676.4 (M+H)⁺.

Step g.

To a solution of compound 26 (150 mg, 0.22 mmol) in dioxane (2 mL) wasadded 4N HCl in dioxane (2 mL) at rt. After stirring at rt overnight,the solvent was removed and the residue was dried in vacuo to give anHCl salt, which was used for the next step without further purification.LC-MS (ESI): m/z 476.2 (M+H)⁺.

Step h.

To a mixture of the HCl salt in DMF (2 mL) was added DIPEA (0.37 mL, 2.3mmol), followed by N-Moc-L-Val-OH (101 mg, 0.58 mmol) and HATU (218 mg,0.58 mmol). After stirring at rt for 30 min, the reaction mixture wasconcentrated and the residue was purified by preparative HPLC to givecompound 26. ¹H NMR (500 MHz, CD₃OD) δ 7.96 (d, 2H, J=11.5), 7.83-7.78(m, 4H), 7.72 (d, 2H, J=8.0), 5.56 (m, 1H), 5.38-5.32 (m, 2H), 4.46-4.42(m, 1H), 4.27-4.26 (m, 1H), 4.21-4.13 (m, 2H), 3.97-3.94 (m, 1H), 3.66(s, 6H), 2.89-2.86 (m, 1H), 2.64-2.62 (m, 2H), 2.34-2.25 (m, 3H),2.01-1.96 (m, 2H), 0.94-0.87 (m, 12H) ppm; LC-MS (ESI): m/z 790.4(M+H)⁺.

Step a.

Referring to Scheme 3-5, a mixture of trichloroacetealdehyde (7.2 g, 48mmol) in water (120 mL) was added Na₂SO₄ (104 g), followed by4-bromobenzenamine (35) in coned. aq. HCl (10 mL) and NH₂OH.HCl (8.8 g,0.13 mol) in H₂O (100 mL). After refluxing for 1 h, the reaction mixturewas cooled to rt. The solid was collected by filtration and dried invacuo to give compound 36 (8.0 g, 91%) as a yellow solid. LC-MS (ESI)m/z: 243.0 (M+H)⁺.

Step b.

To a round-bottomed flask was charged with 20 mL of H₂SO₄ (98%) and thesolution was warmed to 50° C. Subsequently, compound 36 (4.8 g, 20 mmol)was added at such a rate as to keep the temperature between 60 and 70°C. After the completion of adding compound 36, the resulting mixture waswarmed to 80° C. and stirred for another 10 min. The mixture was cooledto rt and poured into ice (200 g). The solid was collected byfiltration, washed with water for several times, and dried in vacuo togive compound 37 (3.6 g, 80% yield) as an orange solid. LC-MS (ESI) m/z:225.9 (M+H)⁺.

Step c.

A mixture of compound 37 (1.35 g, 6.0 mmol), 1-(4-bromophenyl)ethanone(1.14 g, 5.7 mmol), and potassium hydroxide (1.02 g, 18.3 mmol) inethanol (50 mL) was refluxed overnight. The reaction mixture wasconcentrated and the residue was diluted with petroleum ether (100 mL)and water (200 mL). The aqueous phase was isolated, acidified by adding1N HCl, and then extracted with ethyl acetate (50 mL×3). The extractswere combined, washed with brine, and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was dried in vacuo to give crudecompound 38 (1.2 g) as a red solid, which was used for the next stepwithout further purification. LC-MS (ESI) m/z: 405.9 (M+H)⁺.

Step d.

A flask that charged with compound 5 (1.2 g, 2.95 mmol) was heated to300° C. for 30 min under an atmosphere of Ar. The solid was thenpurified by silica gel column chromatography (Petroleum ether/EtOAc=19:1(v/v)) to give compound 39 (160 mg, 15% yield) as a yellow solid. LC-MS(ESI) m/z: 361.9 (M+H)⁺.

Step e.

A mixture of compound 39 (0.11 g, 0.30 mmol), bis(pinacolato)diboron(0.34 g, 1.3 mmol), potassium acetate (0.15 g, 1.5 mmol), andPd(dppf)Cl₂ (50 mg, 0.06 mmol) and dioxane (20 mL) was stirred at 80° C.overnight under an atmosphere of Ar. Subsequently, the reaction mixturewas diluted with EtOAc (100 mL). The resulting mixture was washed withH₂O (50 mL) and dried with anhydrous Na₂SO₄. The solvent was removed andthe residue was purified by silica gel column chromatography (Petroleumether/acetone=10/1 (v/v)) to give compound 40 (0.12 g, 86% yield). LC-MS(ESI) m/z: 458.3 (M+H)⁺. (The corresponding boronic acid was alsoisolated and used as an active intermediate for the next step).

Step f.

A solution of compound 40 (120 mg, 0.26 mmol) in DME/H₂O (3/1 (v/v); 24mL) was sequentially added (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (290 mg, 0.80mmol), NaHCO₃ (220 mg, 2.6 mmol), and Pd(dppf)Cl₂.CH₂Cl₂ (62 mg, 0.064mmol) at rt under an atmosphere of Ar. After stirring at 80° C.overnight under an atmosphere of Ar, the reaction mixture was dilutedwith EtOAc (100 mL). The organic layer was isolated, washed with brine,and dried with anhydrous Na₂SO₄. The solvent was removed and the residuewas purified by silica gel column chromatography (PE/acetone=2/1 (v/v))to give compound 17 (151 mg, 86% yield) as a yellow solid. LC-MS (ESI):m/z 676.4 (M+H)⁺.

Step g.

To a stirred solution of compound 41 (120 mg, 0.18 mmol) in dioxane (2mL) was added 4N HCl/dioxane (2 mL). After stirring at rt overnight, thereaction mixture was concentrated and the residue was dried in vacuo togive an HCl salt, which was used for the next step without furtherpurification. LC-MS (ESI): m/z 476.2 (M+H)⁺.

Step h.

To a mixture of the HCl salt in DMF (2 mL) was added DIPEA (0.3 mL, 1.8mmol), followed by N-Moc-L-Val-OH (79 mg, 0.45 mmol) and HATU (169 mg,0.45 mmol). After stirring at rt for 30 min, the reaction mixture wasslowly poured into H₂O. The solid was collected by filtration andpurified by preparative HPLC to give compound 42. ¹H NMR (500 MHz,CD₃OD) δ 8.96 (d, 2H, J=9.5 Hz), 8.63 (s, 1H), 8.53 (d, 2H, J=10.0 Hz),8.40-8.39 (m, 3H), 8.18 (s, 1H), 8.08 (d, 2H, J=13 Hz), 5.29-5.28 (m,2H), 4.26-4.24 (m, 2H), 4.11-4.10 (m, 2H), 3.99-3.97 (m, 2H), 3.66 (s,6H), 2.60 (m, 2H), 2.30-2.24 (m, 3H), 2.21-2.19 (m, 3H), 2.14-2.09 (m,2H), 1.00-0.83 (m, 12H) ppm; LC-MS (ESI) m/z: 790.4 (M+H)⁺.

Step a.

Referring to Scheme 3-6, a mixture of 4-methoxy-2-nitrobenzaldehyde (42)(1.4 g, 7.7 mmol) and 4-methoxyphenyl acetonitrile (1.13 g, 7.7 mmol)was added to a solution of sodium methylate (0.4 g, 7.7 mmol) inmethanol (10 mL) at rt. After stirring at rt for 5 h, the reactionmixture was filtered. The solid was washed with water and 95% ethanol,respectively, and dried in vacuo to give compound 43 (1.82 g, 77% yield)as a yellow powder. ¹H NMR (500 MHz, CDCl₃) δ 7.90 (d, J=8.5 Hz, 1H),7.85 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.63 (d, J=9.0 Hz, 2H), 7.28 (m,1H), 6.98 (d, J=9.0 Hz, 2H), 3.94 (s, 3H), 3.87 (s, 3H) ppm. LC-MS(ESI): m/z 311.1 (M+H)^(+s.)

Step b.

A solution of compound 43 (15.5 g, 50 mmol) in THF/methanol (5/1 (v/v),240 mL) was added NaBH₄ (2.8 g, 75 mmol) at rt. After stirring at rt for4 h, the reaction mixture was poured into ice water and treated with 1 Naq. HCl. The resulting mixture was extracted with EtOAc (50 mL×2). Theextracts were combined, washed with brine, and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was dried in vacuo togive crude compound 44 (9.8 g), which was used for the next step withoutfurther purification. LC-MS (ESI): m/z 335.1 (M+Na)⁺.

Step c.

A mixture of compound 44 (9.0 g, 29 mmol) and 10% Pd/C (4.5 g) in THF(240 mL) and MeOH (60 mL) was stirred at 45° C. for 48 h under anatmosphere of H₂. The resulting mixture was filtered through CELITE™545; the filtered cake was washed with MeOH (50 mL×3). The filtrate wasconcentrated and the residue was purified by silica gel columnchromatography (Petroleum ether Ethyl acetate 9:1) to give compound 45(5.5 g, 71% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.16 (d,J=8.5 Hz, 2H), 6.91-6.87 (m, 3H), 6.25 (d, J=8.5 Hz, 1H), 6.12 (s, 1H),3.80 (s, 3H), 3.75 (s, 3H), 3.41 (d, J=11.0 Hz, 1H), 3.27 (t, J=11.0 Hz,1H), 3.11-3.05 (m, 1H), 2.90 (d, J=8.0 Hz, 2H) ppm; LC-MS (ESI): m/z270.1 (M+H)⁺.

Step d.

A mixture of compound 45 (2.7 g, 10 mmol) and 10% Pd/C (1.4 g) wasstirred at 270˜280° C. for 30 min under an atmosphere of Ar. The mixturewas purified by silica gel column chromatography (Petroleumether/EtOAc=6/1 (v/v)) to give compound 46 (1.8 g, 68%) as a whitesolid. LC-MS (ESI): m/z 266.1 (M+H)⁺.

Step e.

To a solution of compound 46 (0.80 g, 3.0 mmol) in CH₂Cl₂ (30 mL) wasadded 4 N BBr₃₁CH₂Cl₂ (4.5 mL, 18 mmol) at −40° C. After stirring at rtovernight, the reaction mixture was diluted with water (30 mL). Theresulting mixture was treated with 1 N aq. NaOH solution to adjust thepH to 8, and extracted with EtOAc (60 mL×2). The extracts were combined,washed with brine, and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel chromatography(Petroleum ether/EtOAc=2/1 (v/v)) to give compound 47 (0.7 g, 99%) as awhite solid. LC-MS (ESI): m/z 238.1 (M+H)⁺.

Step f.

To a solution of compound 47 (0.82 g, 3.5 mmol) and pyridine (1.3 g, 16mmol) in CH₂Cl₂ (45 mL) was added and Tf₂O (3.6 g, 13 mmol) at 0° C.After stirring at rt for 30 min, the reaction mixture was concentratedand the residue was purified by silica gel chromatography (Petroleumether/EtOAc=10/1 (v/v)) to give compound 48 (0.40 g, 23%) as a yellowsolid. LC-MS (ESI): m/z 502.1 (M+H)⁺.

Step g.

A mixture of compound 48 (0.40 g, 0.80 mmol), bis(pinacolato)diboron(1.0 g, 4.0 mmol), potassium acetate (0.55 g, 5.6 mmol), and Pd(dppf)Cl₂(200 mg, 0.24 mmol) and dioxane (20 mL) was stirred at 80° C. overnightunder an atmosphere of Ar. Subsequently, the reaction mixture wasdiluted with EtOAc (100 mL). The resulting mixture was washed with H₂O(50 mL) and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was purified by silica gel column chromatography (Petroleumether/acetone=10/1 (v/v)) to give compound 49 (0.20 g, 54% yield). LC-MS(ESI) m/z: 458.3 (M+H)⁺. (The corresponding boronic acid was alsoisolated and used as an active intermediate for the next step).

Step h.

A solution of compound 49 (160 mg, 0.35 mmol) in DME/H₂O (3/1 (v/v); 40mL) was sequentially added (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (388 mg, 1.07mmol), NaHCO₃ (289 mg, 3.44 mmol), and Pd(dppf)Cl₂.CH₂Cl₂ (71 mg, 0.090mmol) at rt under an atmosphere of Ar. After stirring at 80° C.overnight under an atmosphere of Ar, the reaction mixture was dilutedwith EtOAc (100 mL). The organic layer was isolated, washed with brine,and dried with anhydrous Na₂SO₄. The solvent was removed and the residuewas purified by silica gel column chromatography (Petroleumether/acetone=2/1 (v/v)) to give compound 50 (151 mg, 64% yield) as ayellow solid. LC-MS (ESI): m/z 676.4 (M+H)⁺.

Step i.

To a stirred solution of compound 50 (140 mg, 0.21 mmol) in dioxane (2mL) was added 4N HCl in dioxane (2 mL) at rt. After stirring at rtovernight, the reaction mixture was concentrated and the residue wasdried in vacuo to give an HCl salt, which was used for the next stepwithout further purification. LC-MS (ESI): m/z 476.2 (M+H)⁺.

Step j.

To a mixture of the HCl salt in DMF (2 mL) was added DIPEA (0.35 mL, 2.1mmol), followed by N-Boc-L-Val-OH (92 mg, 0.53 mmol), and HATU (200 mg,0.530 mmol). After stirring at rt for 30 min, the reaction mixture waspoured into water. The solid was collected by filtration and purified bypreparative HPLC to give compound 51. ¹H NMR (500 MHz, CD₃OD) δ 9.29(br, 1H), 8.67-8.63 (m, 1H), 8.44-8.41 (m, 1H), 8.29-8.21 (m, 2H), 8.13(s, 2H), 8.01 (s, 2H), 5.31-5.25 (m, 2H), 4.26-4.23 (m, 2H), 4.12 (s,2H), 4.05-3.91 (m, 2H), 3.66 (s, 3H), 3.62 (s, 3H), 2.60 (m, 2H),2.31-1.95 (m, 7H), 1.01-0.86 (m, 12H) ppm; LC-MS (ESI): m/z 790.4(M+H)⁺.

Step a.

Referring to Scheme 3-7, a mixture of compound 52 (9.35 g, 50 mmol),TMS-acetylene (7.35 g, 75 mmol), DIEA (21.0 mL, 150 mmol), CuI (475 mg,2.50 mmol), Pd(PPh₃)₂Cl₂ (3.51 g, 5.0 mmol), and PPh₃ (2.62 g, 10.0mmol) in anhydrous THF (100 mL) was refluxed overnight under anatmosphere of Ar. The reaction mixture was concentrated and the residuewas diluted with water (50 mL) and EtOAc (150 mL). The organic layer waswashed with brine and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(Petroleum cther/EtOAc=10/1 (v/v)) to give compound 53 (10.0 g, 98%) asa yellow oil. LC-MS (ESI): m/z 205.1 (M+H)⁺.

Step b.

A mixture of compound 53 (2.4 g, 11.7 mmol) and K₂CO₃ (4.9 g, 35.3 mmol)in THF (20 mL) and MeOH (20 mL) was stirred at rt for 3 h. The solventwas removed and the residue was diluted with EtOAc (150 mL), washed withbrine, and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was purified by silica gel column chromatography (Petroleumether/acetone=10/1 (v/v)) to give compound 54 (1.3 g, 84%) as a yellowoil. LC-MS (ESI): m/z 133.1 (M+H)⁺.

Step c.

To a solution of compound 55 (25.0 g, 184 mmol) in AcOH (125 mL) wasadded Br₂ (11.0 mL, 220 mmol). After stirring at rt for 4 h, thereaction mixture was filtered. The solid was washed with H₂Oand dried invacuo to give compound 56 (38 g, 96%) as a white solid. LC-MS (ESI): m/z215.0 (M+H)⁺.

Step d.

A mixture of compound 54 (17.9 g, 83.3 mmol), compound 56 (11.0 g, 83.3mmol), CuI (1.59 g, 0.25 mmol), Et₃N (23.00 mL, 166.6 mmol),Pd(PPh₃)₂Cl₂ (2.95 g, 4.20 mmol), and PPh₃ (4.40 g, 16.7 mmol) in DMF(100 mL) was stirred at 40° C. overnight under an atmosphere of N₂. Thereaction mixture was concentrated and the residue was diluted with EtOAc(500 mL). The resulting mixture was washed with brine and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was purifiedby silica gel column chromatography (Petroleum ether/EtOAc=10/1 (v/v))to give compound 57 (9.8 g, 45%). LC-MS (ESI): m/z 267.1 (M+H)⁺.

Step e.

A solution of compound 57 (5.5 g, 21 mmol) in EtOH (100 mL) was addedhydroxylamine hydrochloride (1.73 g, 25.0 mmol) and NaOAc (2.05 g, 25.0mmol), respectively. After stirring at 60° C. for 2 h, the reactionmixture was added K₂CO₃ (4.3 g, 31 mmol) and H₂O (15 mL). The resultingmixture was refluxed for 12 h and then concentrated. The residue wasdissolved in EtOAc and the resulting mixture was washed with brine anddried with anhydrous Na₂SO₄. The solvent was removed and the residue wasdried in vacuo to give crude compound 58 (5.8 g). LC-MS (ESI): m/z 282.1(M+H)⁺.

Step f.

A mixture of compound 58 (100 mg, 0.36 mmol) and 5% Pd/C (75 mg) in EtOH(25 mL) was stirred at rt overnight under an atmosphere of H₂. Thereaction mixture was filtered through CELITE™ 545. The filtered cake waswashed MeOH (25 mL×3). The filtrate was concentrated and the residue waspurified by silica gel column chromatography to give compound 59 (50 mg,53%). LC-MS (ESI): m/z 266.1 (M+H)⁺.

Step g.

To a solution of compound 59 (2.0 g, 7.5 mmol) in CH₂Cl₂ (75 mL) wasadded 4N BBr₃ in CH₂Cl₂ (12 mL, 45 mmol) at −40° C. under an atmosphereof N₂. After stirring at rt overnight, the reaction was quenched byadding water (10 mL). Subsequently, the mixture was treated withsaturated aqueous NaHCO₃ to adjust the pH value to 8. The organic layerwas washed with brine and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(Petroleum ether/EtOAc=2/1 (v/v)) to give compound 60 (1.36 g, 76%) as awhite solid. LC-MS (ESI): m/z 238.1 (M+H)⁺.

Step h.

To a solution of substrate 7 (1.36 g, 5.7 mmol) and pyridine (2.03 g,25.7 mmol) in CH₂Cl₂ (120 mL) was added Tf₂O (5.84 g, 20.7 mmol) inCH₂Cl₂ (30 mL) at 0° C. After stirring at 0° C. for 30 min, the reactionmixture was concentrated and the residue was purified by silica gelcolumn chromatography (Petroleum ether/EtOAc=10/1 (v/v)) to givecompound 61 (2.4 g, 84%) as a yellow solid. LC-MS (ESI): m/z 502.0(M+H)⁺.

Step i.

A mixture of compound 61 (2.0 g, 4.0 mmol), bis(pinacolato)diboron (5.1g, 20 mmol), potassium acetate (2.7 g, 28 mmol), and Pd(dppf)Cl₂ (0.98g, 1.2 mmol) and dioxane (80 mL) was stirred at 80° C. overnight underan atmosphere of Ar. Subsequently, the reaction mixture was diluted withEtOAc (100 mL). The resulting mixture was washed with H₂O (50 mL) anddried with anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleumether/acetone=10/1 (v/v)) to give compound 62 (986 mg, 54% yield). LC-MS(ESI) m/z: 458.3 (M+H)⁺. (The corresponding boronic acid was alsoisolated and used as an active intermediate for the next step).

Step j.

A solution of compound 62 (1.7 g, 3.7 mmol) in DME/H₂O (3/1 (v/v); 40mL) was sequentially added (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (3.70 g, 10.0mmol), NaHCO₃ (2.7 g, 32 mmol), and Pd(dppf)Cl₂ (0.65 mg, 0.80 mmol) atrt under an atmosphere of Ar. After stirring at 80° C. overnight underan atmosphere of Ar, the reaction mixture was diluted with EtOAc (150mL). The organic layer was isolated, washed with brine, and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was purifiedby silica gel column chromatography (Petroleum ether/acetone=2/1 (v/v))to give compound 63 (650 mg, 26%) as a yellow solid. LC-MS (ESI): m/z676.4 (M+H)^(|).

Step k.

To a stirred solution of compound 63 (200 mg, 0.3 mmol) in dioxane (3mL) was added 4N HCl in dioxane (3 mL) at rt. After stirring at rtovernight, the reaction mixture was concentrated and the residue wasdried in vacuo to give an HCl salt, which was used for the next withoutfurther purification. LC-MS (ESI): m/z 476.2 (M+H)⁺.

Step l.

Subsequently, a mixture of the HCl salt in DMF (3 mL) was added DIPEA(0.5 mL, 3.0 mmol), followed by N-Moc-L-Val-OH (130 mg, 0.740 mmol), andHATU (281 mg, 0.740 mmol). After stirring at rt for 30 min, the reactionmixture was poured into H₂O. The solid was collected by filtration andpurified by preparative HPLC to give compound 64. ¹H NMR (500 MHz,CD₃OD) δ ppm 9.80 (s, 1H), 8.87-8.71 (m, 2H), 8.41-8.18 (m, 6H),8.05-7.80 (m, 3H), 5.30-5.27 (m, 2H), 4.25 (s, 2H), 4.12 (s, 2H),4.03-3.90 (m, 2H), 3.66 (s, 6H), 2.61 (s, 2H), 2.31-2.08 (m, 8H),1.09-0090 (m, 12H); LCMS (ESI): m/z 790.4 (M+H)⁺.

Step a.

Referring to Scheme 3-8, to a solution of 132 (3.70 g, 14.7 mmol) in DMF(50 mL) at rt, N,O-Dimethylhydroxylamine hydrochloride (1.46 g, 15.0mmol), HATU (6.15 g, 16.2 mmol), and Et₃N (2.22 g, 22.0 mmol) wereadded. After stirring at rt for 24 h, the reaction mixture wasconcentrated and the residue was diluted with DCM (150 mL). The mixturewas washed with saturated aqueous NH₄Cl and brine, respectively, anddried with anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleum ether/EtOAc=4/1(v/v)) to give compound 133 (3.78 g, 87% yield) as a yellow solid. LC-MS(ESI): m/z 295.0 (M+H)⁺.

Step b.

To a solution of compound 133 (3.53 g, 12.0 mmol) in THF (80 mL) wasslowly added 3M MeMgCl in THF (6 mL) at 0° C. After stirring at 0° C.for 1 h and then at rt for another 1 h, the reaction was quenched byadding saturated aqueous NH₄Cl. The reaction mixture was concentratedand the residue was added saturated aqueous NaHCO₃ (25 mL) and EtOAc(100 mL). The organic phase was washed with brine and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give compound 134 (3.0 g, 100%) as a white solid. LC-MS (ESI):m/z 250.0 (M+H)⁺.

Step c.

To a solution of compound 134 (2.80 g, 11.2 mmol) in DCM (80 mL) wasadded ^(i)Pr₂NEt (5.79 g, 44.8 mmol). The mixture was cooled to 0° C.and TMSOTf (7.47 g, 33.6 mmol) was drop-wisely added. After stirring at0° C. for 30 min and then at rt for another 1 h, the reaction mixturewas washed with saturated aqueous NaHCO₃ and brine, respectively, anddried with anhydrous Na₂SO₄. The solvent was removed and the residue wasdried in vacuo to give crude compound 135 (3.6 g), which was used forthe next step without further purification. LC-MS (EST): m/z 322.0(M+H)⁺.

Step d.

To a solution of compound 135 (3.60 g, 11.2 mmol) in THF (60 mL) wasdrop-wisely added solution of NBS (1.79 g, 10.1 mmol) in THF (20 mL) at0° C. After stirring at 10° C. for 1 h, the reaction mixture wasconcentrated and the residue was diluted with DCM (150 mL). The mixturewas washed with brine and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was dried in vacuo to give crude compound 136(3.6 g), which was used of the next step without further purification.LC-MS (ESI): m/z 327.9 (M+H)^(|).

Step e.

To a solution of compound 136 (3.6 g, 10.9 mmol) in EtOAc (100 mL) atrt, (S)—N-Boc-Pro-OH (2.47 g, 11.5 mmol) and Et₃N (3.31 g, 32.7 mmol)were added. After stirring at rt for 5 h, the reaction mixture waswashed with saturated aqueous NaHCO₃ and brine, respectively, and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue was driedin vacuo to give crude compound 137 (5.0 g), which was used for the nextstep without further purification. LC-MS (ESI): m/z 463.1 (M+H)⁺.

Step f.

A mixture of crude compound 137 (5.0 g) and NH₄OAc (8.39 g, 109 mmol) intoluene (100 mL) was stirred at 115° C. overnight. The solvent wasremoved and the residue was diluted with EtOAc (200 mL). The mixture waswashed with water and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(Petroleum ether/EtOAc=3/1 (v/v)) to give compound 138 (1.2 g, 25%) as awhite solid. LC-MS (ESI): m/z 443.1 (M+H)⁺.

Step g.

To a mixture of compound 138 (442 mg, 1.00 mmol), compound 139 (546 mg,1.10 mmol), and NaHCO₃ (336 mg, 4.00 mmol) in 1,2-dimethoxyethane (8 mL)and H₂O (2 mL) was added Pd(dppf)Cl₂. CH₂CH₂Cl₂ (163 mg, 0.20 mmol)under an atmosphere of N₂. After stirring at 80° C. overnight, thereaction mixture was concentrated and the residue was diluted with EtOAc(50 mL) and H₂O (10 mL). The organic phase was washed with brine anddried with anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleum ether/EtOAc=1/2(v/v)) to give compound 140 (500 mg, 68% yield) as a yellow solid. LC-MS(ESI): m/z 733.4 (M+H)⁺.

Step h.

To a solution of compound 140 (139 mg, 0.19 mmol) in dioxane (2 mL) wasadded 4N HCl in dioxane (2.0 mL). After stirring at rt for 2 h, thereaction mixture was concentrated and the residue was dissolved in water(5 mL) and added saturated aqueous NaHCO₃ to adjust pH value to 8. Theresulting mixture was saturated with NaCl and extracted with DCM (15mL×5). The extracts were combined and dried with dried with anhydrousNa₂SO₄. The solvent was removed and the residue was dried in vacuo togive a free base, which was used for the next step without furtherpurification. LC-MS (ESI): m/z 633.3 (M+H) H)⁺.

Step i.

Subsequently, the free base was dissolved in DCM (5 mL) and the mixturewas added N-Moc-L-Val-OH (40 mg, 0.23 mmol) and DIC (29 mg, 0.23 mmol).After stirring at rt for 20 min, the reaction mixture was concentratedand the residue was purified by preparative HPLC to give compound 141.LC-MS (ESI): m/z 790.4 (M+H)⁺.

Example 4 Synthesis of compounds of Formula IIe

Step a.

Referring to Scheme 4-1, a solution of compound 27 (5.0 g, 20 mmol) inCH₃CN (200 mL) was added EDCI (5.8 g, 30 mmol), HOBt (675 mg, 30 mmol),MeNH(OMe).HCl (2.93 g, 30 mmol), and Et₃N (6.1 g, 60 mmol) at rt. Afterstirring at rt for 3 h, the reaction mixture was concentrated and theresidue was purified by silica gel column chromatography (Petroleumether/EtOAc=5/1 (v/v)) to give compound 28 (5.4 g, 92% yield) as a whitesolid. LC-MS (ESI): m/z 294.0 (M+H)⁺.

Step b.

To a solution of compound 28 (2.9 g, 10 mmol) in THF (100 mL) was slowlyadded 3M MeMgCl in THF (20 mmol) at 0° C. under an atmosphere of N₂.After stirring at 0° C. for 1 h and then at rt for 1 h, the reaction wasquenched by adding several drops of aq. NH₄Cl. The reaction mixture wasconcentrated and the residue was diluted with EtOAc (100 mL). Theorganic phase was washed with sat. aq. NaHCO₃ and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was purified by silicagel column chromatography (Petroleum ether/AcOEt=10:1 (v/v)) to givecompound 29 (2.3 g, 92% yield). LC-MS (ESI): m/z 249.0 (M+H)⁺.

Step c.

To a solution of 29 (1.84 g, 7.4 mmol) in DCM (100 mL) was drop-wiselyadded Br₂ (18.8 g, 14.7 mmol) at 0° C. After stirring at 0° C. for 30min, the reaction mixture was warmed to rt with stirring for another 2h. Subsequently, the reaction mixture was respectively washed withwater, and saturated aqueous NaHCO₃, and the organic phase was driedwith anhydrous Na₂SO₄. The solvent was removed and the residue was driedin vacuo to give crude compound 30 (2.0 g) as a yellow solid, which wasused for the next step without further purification. LC-MS (ESI): m/z326.9 (M+H)⁺.

Step d.

A solution of compound 30 (1.95 g, 5.9 mmol) in DCM (50 mL) was addedN-Boc-L-Pro-OH (1.6 g, 7.3 mmol) and Et₃N (1.7 mL, 12.2 mmol) at rt.After stirring st rt for 2 h, the reaction mixture was washed withsaturated NH₄Cl, and brine, respectively; the organic phase was driedwith anhydrous Na₂SO₄. The solvent was removed and the residue was driedin vacuo to give crude compound 31 (2.4 g), which was used for the nextstep without further purification. LC-MS (ESI): m/z 462.1 (M+H)⁺.

Step e.

A mixture of compound 31 (2.4 g, 5.2 mmol) and NH₄OAc (4.0 g, 52 mmol)in toluene (52 mL) stirred at 110° C. overnight. Subsequently, thereaction mixture was cooled to rt and diluted with EtOAc (100 mL). Themixture was washed with saturated aqueous Na₂CO₃ (50 mL×2), and brine,respectively; the organic phase was dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (Petroleum ether/EtOAc=1/1 (v/v)) to give compound 32(1.4 g, 62%) as a yellow solid. LC-MS (ESI): m/z 442.1 (M+H)⁺.

Step f.

To a mixture of compound 32 (1.0 g, 2.3 mmol), (S)-tert-butyl2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(1.0 g, 2.3 mmol), and NaHCO₃ (0.76 g, 9.0 mmol) in 1,2-dimethoxyethane(30 mL) and H₂O (10 mL) was added Pd(dppf)Cl₂ (277 mg, 0.34 mmol) underan atmosphere of N₂. After stirring at 80° C. overnight under anatmosphere of N₂, the reaction mixture was concentrated. The residue wasdiluted with H₂O (50 mL) and the aqueous phase was extracted with EtOAc(50 mL×3). The extracts were combined and washed with brine and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleum ether/EtOAc=5/2(v/v)) to give compound 33 (1.0 g, 78% yield) as a yellow solid. LC-MS(ESI): m/z 675.4 (M+H)⁺.

Step g.

To a stirred solution of compound 33 (250 mg, 0.37 mmol) in dioxane (3mL) was drop-wisely added 4.0N HCl in dioxane (3 mL) at rt. Afterstirring at rt for 4 h, the reaction mixture was concentrated and theresidue was dried in vacuo to give an HCl salt, which was used for thenext step without further purification. LC-MS (ESI): m/z 475.3 (M+H)⁺.

Step h.

Subsequently, the HCl salt was suspended in THF (5 mL) and DIPEA (0.35mL) and N-Moc-L-Val-OH (130 mg, 0.74 mmol) at rt. After stirring at rtfor 15 min, HATU (340 mg, 0.89 mmol) was added and the resultingreaction mixture was stirred at rt for another 2 h. The solvent wasremoved and the residue was purified by preparative HPLC to givecompound 34. ¹H NMR (500 MHz, CDCl₃) δ 8.04-8.06 (m, 1H), 7.96-7.99 (m,2H), 7.91-7.92 (m, 2H), 7.79 (s, 1H), 7.70-7.71 (m, 2H), 7.66-7.67 (m,2H), 7.60-7.61 (m, 2H), 5.29-5.31 (m, 2H), 4.27 (s, 2H), 4.13 (s, 2H),3.92 (s, 2H), 3.68 (s, 6H), 2.63 (s, 2H), 2.17-2.32 (m, 6H), 2.12 (s,2H), 0.93-0.97 (m, 12H) ppm; LC-MS (ESI): m/z 789.4 (M+H)⁺.

Example 5 Synthesis of compounds of Formula IIIl

Step a.

Referring to Scheme 5-1, a mixture of compound 65 (300 mg, 1.05 mmol),(S)-tert-butyl2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.14 g, 2.75 mmol), and NaHCO₃ (740 mg, 8.80 mmol) in1,2-dimethoxyethane (30 mL) and water (10 mL) were added Pd(dppf)Cl₂(179 mg, 0.220 mmol) at rt under an atmosphere of N₂. After stirring at80° C. overnight, the reaction mixture was concentrated. The residue wasdiluted with DCM (100 mL) and water (25 mL). The organic layer waswashed with brine and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(Petroleum ether/acetone=2/1 (v/v)) to give compound 66 (650 mg, 86%).LC-MS (ESI): m/z 699.4 (M+H)⁺.

Step b.

To a solution of compound 66 (110 mg, 0.16 mmol) in dioxane (2 mL) wasadded 4.0 N HCl in dioxane (2 mL) at rt. After stirring at rt for 3 h,the reaction mixture was concentrated and the residue was dried in vacuoto give an HCl salt, which was used directly for the next step withoutfurther purification. LC-MS (ESI): m/z 499.3 (M+H)⁺.

Step c.

Subsequently, the HCl salt was dissolved in DMF (2 mL), followed byadding DIPEA (207 mg, 16 mmol), N-Moc-L-Val-OH (68 mg, 0.39 mmol), andHATU (148 mg, 0.39 mmol) at rt. After stirring at rt for 15 min, thereaction mixture was added into water. The solid was collected byfiltration and purified by preparative HPLC to give compound 67. LC-MS(ESI) m/z 813.4 (M+H)⁺.

Example 6 Synthesis of compounds of Formula IIId

Step a.

Referring to Scheme 6-1, a mixture of compound 70 (8.00 g, 35.7 mmol,purchased from Aldrich Chemicals, Milwaukee, Wis., USA),bis(pinacolato)diboron (10.9 g, 42.8 mmol), K₂CO₃ (10.50 g, 107.1 mmol)in 1,4-dioxane (600 mL) was added Pd(dppf)Cl₂ (2.9 g, 3.6 mmol) at rtunder an atmosphere of N₂. After stirring at 80° C. for 3 h under anatmosphere of N₂, the reaction mixture was cooled to rt and filteredthrough Celiirt®545. The filtered cake was washed with EtOAct (100mL×3). The filtrate was concentrated and the residue was diluted withEtOAc (500 mL). The resulting mixture was washed with brine and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleumether/Acetone=1/1 (v/v)) to give compound 71 (8.28 g, 86% yield) as alight brown solid. LC-MS (ESI) m/z 272.1 (M+H)⁺.

Step b.

To a mixture of compound 71 (5.90 g, 21.8 mmol), (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (9.50 g, 26.2mmol), NaHCO₃ (7.30 g, 87.2 mmol) in 1,2-dimethoxyethane (500 mL) andwater (150 mL) was added Pd(dppf)Cl₂ (3.6 g, 4.4 mmol) under anatmosphere of N₂. After stirring at 80° C. overnight, the reactionmixture was concentrated and the residue was diluted with EtOAc (250 mL)and water (50 mL). The organic layer was washed with brine and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (DCM/MeOH=5/1 (v/v)) togive compound 72 (5.30 g, 64% yield) as a yellow solid. LC-MS (ESI) m/z381.2 (M+H)⁺.

Step c.

To a solution of compound 72 (2.0 g, 5.26 mmol) in 40 mL pyridine wasdrop-wisely added Tf₂O (3.71 g, 13.1 mmol) at 0° C. After stirring at 0°C. for 1 h and at rt for 3 h, the reaction mixture was concentrated. Theresidue was purified by silica gel column chromatography (Petroleumether/acetone=4/1 (v/v)) to give compound 73 (2.04 g, 60% yield) as ayellow solid. LC-MS (ESI) m/z 645.1 (M+H)⁺.

Step d.

To a mixture of compound 73 (500 mg, 0.78 mmol), methyl(S)-3-methyl-1-oxo-1-((S)-2-(6-(4,4,5,5-tertamethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)butan-2-ylcarbamate(74) (419 mg, 0.89 mmol), and NaHCO₃ (299 g, 3.56 mmol) in1,2-dimethoxyethane (60 mL) and water (20 mL) was added Pd(dppf)Cl₂ (147mg, 0.18 mmol) at rt under an atmosphere of N₂. After stirring at 80° C.overnight under an atmosphere of N₂, the reaction mixture wasconcentrated. The residue was diluted with EtOAc (100 mL) and water (25mL). The organic layer was washed with brine and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was purified by silicagel column chromatography (Petroleum ether/acetone=1:1 (v/v)) to givecompound 75 (0.40 g, 64% yield) as a yellow solid. LC-MS (ESI) m/z 707.4(M+H)⁺.

Step e.

To a solution of compound 75 (114 mg, 0.161 mmol) in dioxane (2 mL) wasadded 4N HCl in dioxane (2 mL) at rt. After stirring at rt for 3 h, thereaction mixture was concentrated and the residue was dried in vacuo togive an HCl salt, which was used for the next step without furtherpurification. LC-MS (ESI) m/z 607.3 (M+H)⁺.

Step f.

Subsequently, the HCl salt was dissolved in DMF (2 mL), followed byadding Et₃N (0.11 mL, 0.81 mmol), N-Moc-L-Val-OH (32 mg, 0.18 mmol), andHATU (69 mg, 0.18 mmol) at rt. After stirring at rt for 1 h, thereaction mixture was concentrated and the residue was purified bypreparative HPLC to give compound 76. LC-MS (ESI): m/z 764.4 (M+H)⁺.

Step a.

Referring to Scheme 6-2, a solution of compound 78 (50.0 g, 0.30 mol) inTHF (500 mL) and H₂O (500 mL) was added K₂CO₃ (83 g, 0.60 mol) and(Boc)₂O (73.0 g, 0.330 mol). After stirring at rt overnight, thereaction mixture was concentrated and the residue was extracted withEtOAc (250 mL×3). The extracts were combined, washed with brine, anddried with anhydrous Na₂SO₄. The solvent was removed and the residue wasdried in vacuo to give crude compound 78 (62 g), which was used for thenext step without further purification. LC-MS (ESI) m/z 230.1 (M+H)⁺.

Step b.

To a solution of compound 78 (60.0 g, 260 mmol) in EtOH (1 L) was slowlyadded NaBH₄ (50.0 g, 1.30 mol) at rt. After stirring at rt overnight,the reaction was quenched by adding acetone (10 mL). The resultingmixture was concentrated and the residue was diluted with EtOAc (500mL). The mixture was washed with brined and dried in vacuo. The solventwas removed and the residue was purified by silica gel columnchromatography (Petroleum ether/EtOAc=1/1 (v/v)) to give compound 79(42.0 g, 80% yield) as a white solid. LC-MS (ESI) m/z 202.1 (M+H)⁺.

Step c.

To a solution of compound 79 (30.0 g, 150 mmol) and DMSO (35.0 g, 450mmol) in DCM (1 L) was added oxalyl chloride (28.0 g, 220 mmol) at −78°C. After stirring at −78° C. for 4 h, the reaction mixture was addedEt₃N (60.0 g, 600 mol) and the resulting mixture was stirred for another1 h at −78° C. Subsequently, the reaction was quenched by adding H₂O.The organic layer was separated and the aqueous layer was extracted withDCM (200 mL×2). The extracts were combined, washed with brine, and driedwith Na₂SO₄. The solvent was removed and the residue was dried in vacuoto give crude compound 80 (22.0 g) as a colorless oil, which was usedimmediately without further purification. LC-MS (ESI) m/z 200.1 (M+H)⁺.

Step d.

A mixture of compound 80 (7.7 g, 38.5 mmol), 6-bromopyridine-2,3-diamine(8.0 g, 42.8 mmol) (PCT Intl. Appl. WO 2008021851), and iodine (1.08 g,4.28 mmol) in AcOH (30 mL) was stirred at rt overnight. The reactionmixture was neutralized by adding saturated aqueous NaHCO₃. Theresulting mixture was extracted with EtOAc (200 mL×3). The extracts werecombined, washed with brine, and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (DCM/MeOH=80/1 (v/v)) to give compound 81 (7.8 g, 55%yield). LC-MS (ESI) m/z 367.1 (M+H)⁺.

Step e.

A mixture of compound 82 (10.0 g, 20.1 mmol), bis(pinacolato)diboron(7.65 g, 30.1 mmol), potassium acetate (6.89 g, 70.3 mmol), andPd(dppf)Cl₂.CH₂Cl₂ (886 mg, 1.0 mmol) in 1,4-dioxane (200 mL) wasstirred at 80° C. for 3 h under an atmosphere of N₂. The reactionmixture was filtered through CELITE™ 545 and the filtered cake waswashed with EtOAc (200 mL×3). The filtrate was washed with brine anddried with anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (DCM/MeOH=50/1 (v/v)) togive compound 83 (9.8 g, 89% yield) as a white solid: LC-MS (ESI) m/z547.3 (M+H)⁺.

Step f.

A mixture of compound 81 (2.0 g, 5.4 mmol), compound 83 (2.9 g, 5.4mmol), NaHCO₃ (1.60 g, 18.9 mmol), and Pd(dppf)Cl₂.CH₂Cl₂ (239 mg, 0.27mmol) in 1, 2-dimethoxyethane (90 mL) and water (30 mL) was stirred at80° C. overnight under an atmosphere of N₂. The reaction mixture wasconcentrated and the residue was added DCM (200 mL) and water (50 mL).The organic pahse was washed with brine and dried with anhydrous Na₂SO₄.The solvent was removed and the residue was purified by silica gelcolumn chromatography (DCM/MeOH=80/1 (v/v)) to give compound 84 (1.5 g,40% yield) as a yellow solid. LC-MS (ESI) m/z 707.4 (M+H)⁺.

Step g.

To a solution of compound 84 (200 mg, 0.28 mmol) in 3 mL dioxane wasadded 4N HCl in dioxane (3 mL). After stirring at rt for 3 h, thereaction mixture was concentrated and the residue was dried in vacuo togive an HCl salt, which was used for the next step without furtherpurification. LC-MS (ESI) m/z 607.3 (M+H)⁺.

Step h.

Subsequently, the HCl salt was dissolved in DMF (3 mL), and theresulting mixture was added Et₃N (0.20 mL, 1.4 mmol), N-Moc-L-Val-OH (55mg, 0.31 mmol), and HATU (118 mg, 0.31 mmol). After stirring at rt for 1h, the reaction mixture was concentrated and the residue was purified bypreparative HPLC to give compound 85. LC-MS (ESI): m/z 764.4 (M+H)⁺.

Step a.

Referring to Scheme 6-3, to a solution of N-Boc-L-Pro-OH (29 g, 135mmol) and DIPEA (29 g, 225 mmol) in THF (500 mL) was added HATU (51 g,135 mmol) at rt. After stirring at rt for 10 min,4-bromobenzene-1,2-diamine (95) (25 g, 135 mmol) was added and theresulting solution was stirred at rt for another several hours.Subsequently, the reaction mixture was concentrated and the residue wasdiluted with EtOAc (500 mL). The resulting mixture was washed with waterfor several times (100 mL×3) and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was dried in vacuo to give a mixtureof crude compounds 96 and 96′, which were used for the next step withoutfurther purification. LC-MS (ESI): m/z 384.1 (M+H)⁺.

Step b.

A mixture of crude compounds 96 and 96′ obtained from the reaction abovein AcOH (1000 mL) was stirred at 40° C. for 12 h. Subsequently, thereaction mixture was carefully neutralized by adding saturated aqueoussodium bicarbonate solution to adjust the pH value to 8. The resultingmixture was extracted with EtOAc for several times (250 mL×3). Theextracts were combined, washed with water, and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was purified by silicagel chromatography (Petroleum ether/EtOAc=4/1 (v/v)) to give 97 (35 g,71% yield, two steps from 95) as a yellow solid. LC-MS (ESI): m/z 366.1(M+H)⁺.

Step c.

A mixture of compound 97 (10.0 g, 27.3 mmol), trimethylsilylacetylene(4.0 g, 41.0 mmol), DIPEA (3.5 g, 27.3 mmol), CuI (220 mg, 1.15 mmol),PPh₃ (1.2 g, 4.6 mmol), and Pd(PPh₃)₂Cl₂ (1.6 g, 2.3 mmol) in anhydrousTHF (200 mL) was refluxed overnight under an atmosphere of N₂. Thereaction mixture was concentrated and the residue was diluted with EtOAc(250 mL). The mixture was washed with brine and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was purified by silicagel column chromatography (Petroleum ether/EtOAc=3/1 (v/v)) to compound98 (7.8 g, 85% yield). LC-MS (ESI): m/z 384.2 (M+H)⁺.

Step d.

A mixture of compound 98 (7.7 g, 20 mmol) and K₂CO₃ (27.6 g, 0.2 mol) inTHF (150 mL) and MeOH (150 mL) was stirred at rt for 3 h. The reactionmixture was filtered through CELITE™ 1545 and the filtered cake waswashed with EtOAc (100 mL×3). The filtrate was concentrated and theresidue was diluted with DCM (250 mL). The mixture was washed withbrined and ried with anhydrous Na₂SO₄. The solvent was removed and theresidue was purified by silica gel column chromatography (Petroleumether/acetone=2/1 (v/v)) to give compound 99 (4.7 g, 75% yield). LC-MS(ESI): m/z 312.2 (M+H)⁻.

Step e.

To a solution of m-hydroxybenzaldehyde (100) (30.0 g, 0.24 mol) in dryCHCl₃ (245 mL) was slowly added bromine (12.36 mL, 0.24 mol) over 40-45min at rt. After completion of the addition, the reaction mixture wasstirred at rt for 3 h. Subsequently, saturated aqueous NaHCO₃ wascarefully added to neutralize the mixture. The organic layer was washedwith brine and dried with Na₂SO₄. The solvent was removed and theresidue was dried in vacuo to give crude compound 101 (37 g) as a brownsolid. LC-MS (ESI): m/z 200.9 (M+H)⁺.

Step f.

To a solution of compound 101 (10 g, 49.8 mol) in anhydrous THF/DMF (5/1(v/v), 120 mL) was added NaH (2.0 g, 51 mmol, 60% dispersion in mineraloil) at 0° C. under an atmosphere of N₂. After stirring at rt for 30min, the mixture was added benzyl bromide (8.7 mL, 73 mmol) over 20-25min. The resulting mixture was stirred at rt overnight and the reactionwas quenched by adding saturated aqueous NH₄Cl (50 mL). The reactionmixture was concentrated and the residue was diluted with EtOAc (150 mL)and water (50 mL). The organic phase was washed with brine and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleum ether/EtOAc=10/1(v/v)) to give compound 102 (11 g, 77% yield). LC-MS (ESI): m/z 291.0(M+H)⁺.

Step g.

A mixture of compound 99 (2.80 g, 9.0 mmol), compound 102 (2.6 g, 9.0mmol), Pd(PPh)₂Cl₂ (6.3 g, 0.9 mmol), CuI (2.55 g, 1.34 mmol), Et₃N (2.5mL, 18 mmol), and PPh₃ (4.7 g, 1.8 mmol) in DMF (100 mL) was stirred at60° C. for 12 h. Subsequently, the reaction mixture was concentrated.The residue was diluted with EtOAc (150 mL) and water (50 mL). Theorganic phase was washed with brined and dried with anhydrous Na₂SO₄.The solvent was removed and the residue was purified by silica gelcolumn chromatography (Petroleum ether/EtOAc=10/1 (v/v)) to givecompound 103 (4.0 g, 86% yield). LC-MS (ESI): m/z 522.2 (M+H)⁺.

Step h.

A solution of compound 103 (4.1 g, 7.9 mmol) in EtOH (100 mL) was addedhydroxylamine hydrochloride (650 mg, 9.4 mmol) and NaOAc (770 mg, 9.4mmol), respectively, at rt. After stirring at 60° C. for 2 h, thereaction mixture was added K₂CO₃ (1.64 g, 11.85 mmol) and water (20 mL).The resulting mixture was refluxed for 12 h. Subsequently, the reactionmixture was concentrated and the residue was diluted with EtOAc (200 mL)and water (20 mL). The organic phase was washed with brine and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleumether/Acetone=5/1 (v/v) to DCM/MeOH=5/1 (v/v)) to give compound 104 (1.5g, 36% yield). LC-MS (ESI): m/z 537.2 (M+H)⁺.

Step i.

A mixture of compound 104 and 10% Pd/C (1.5 g) in MeOH (50 mL) wasstirred at rt overnight under an atmosphere of H₂. Subsequently, thereaction mixture was filtered through CELITE™ 545 and the filtered cakewas washed with MeOH (50 mL×3). The filtrate was concentrated and theresidue was purified by silica gel column chromatography to givecompound 105 (670 mg, 56% yield). LC-MS (ESI): m/z 431.2 (M+H)⁺.

Step j.

To a solution of compound 105 (650 mg, 1.5 mmol) in anhydrous pyridine(711 mg, 9.0 mmol) was added Tf₂O (1.07 g, 3.8 mmol) at 0° C. Afterstirring at rt overnight, the reaction mixture was concentrated and theresidue was diluted with EtOAc (100 mL). The mixthre was washed withbrine and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was purified by silica gel column chromatography (Petroleumether/EtOAc=5/1 (v/v)) to give compound 106 (720 mg, 69% yield). LC-MS(ESI): m/z 695.1 (M+H)⁺.

Step k.

A mixture of compound 106 (410 mg, 0.6 mmol), bis(pinacolato)diboron(227 mg, 0.9 mmol), PdCl₂(dppf).CH₂Cl₂ (100 mg, 0.12 mmol), and KOAc(235 mg, 2.4 mmol) in dioxane (15 mL) was stirred at 80° C. for 1 hunder an atmosphere of N₂. The reaction mixture was used for the nextstep without any work-up. LC-MS (ESI): m/z 673.2 (M+H)⁺.

Step l.

To the above reaction mixture was added (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (370 mg, 1.02mmol), followed by NaHCO₃ (201 mg, 2.4 mmol), 1,2-dimethoxyethane (4mL), water (2 mL), and Pd(dppf)Cl₂.CH₂Cl₂ (100 mg, 0.12 mmol) under anatmosphere of N₂. After stirring at 80° C. for 2 h under an atmosphereof N₂, the reaction mixture was added K₂CO₃ (691 mg, 5 mmol) and MeOH(20 mL). After stirring at rt for 30 min, the mixture was concentrated.The residue was diluted with EtOAc (150 mL) and water (50 mL). Theorganic layer was washed with brine and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (Petroleum ether/EtOAc=5/1 (v/v)) to give compound 108(140 mg, 36% yield; two steps from compound 107). LC-MS (ESI) m/z 650.3(M+H))⁺.

Step m.

To a solution of compound 108 (135 mg, 0.2 mmol) in dioxane (2 mL) wasadded 4 N HCl in dioxane (2 mL) at rt. After stirring at rt overnight,the reaction mixture was concentrated and the residue was dried in vacuoto give an HCl salt, which was used for the next step without furtherpurification. LCMS (ESI): m/z 450.2 (M+H)⁺.

Step n.

Subsequently, the HCl salt was dissolved in DMF (2 mL) and the resultingmixture was added DIPEA (0.33 mL, 2.0 mmol), N-THPoc-L-Val-OH (108 mg,0.50 mmol), and HATU (190 mg, 0.50 mmol). After stirring at rt for 15min, the reaction mixture was added into ice water. The solid wascollected by filtration and purified by preparative HPLC to givecompound 109. LC-MS (ESI): m/z 848.4 (M+H)⁺.

Step a.

Referring to Scheme 6-4, to a solution of(S)-4-(tert-butoxycarbonyl)morphine-3-carboxylic acid (4.1 g, 22.0 mmol)and DIPEA (4.3 g, 33.0 mmol) in THF (100 mL) was added compound 95 (4.6g, 20.0 mmol) at rt. After stirring for 5 min, the reaction mixture wasadded HATU (7.6 g, 20.0 mmol) was added and the resulting mixture wasstirred at rt for 2 h. The reaction mixture was concentrated and theresidue was diluted with EtOAc (200 mL) and water (50 mL). The organicphase was washed with brine and dried with anhydrous Na₂SO₄. The solventwas removed and the residue was dried in vacuo to give a crude mixtureof compounds 110 and 110′ (10 g), which was used for the next stepwithout further purification. LC-MS (ESI) m/z 400.1 (M+H)⁺.

Step b.

A mixture of compounds 110 and 110′ (10 g) in AcOH (50 mL) was stirredat 40° C. for 16 h. Subsequently, the reaction mixture was added intoice water (200 mL) and neutralized by adding saturated aqueous Na₂CO₃ toadjust pH value to pH 8. The resulting mixture was extracted with EtOAc(100 mL×3) and the extracts were combined, washed with brine, and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleum ether/EtOAc=1/3(v/v)) to give compound 111 (4.5 g, 60% yield; two steps from 95) as ayellow solid. LC-MS (ESI) m/z 382.1 (M+H)⁺.

Step c.

A solution of 1-(6-bromonaphthalen-2-yl)-2-chloroethanone (112) (27.0 g,95.2 mmol) in DCM (200 mL) was added(S)-4-(tert-butoxycarbonyl)morphine-3-carboxylic acid (20.0 g, 86.6mmol) and Et₃N (60.0 mL, 433 mmol), respectively. After stirring at 45°C. overnight, the reaction mixture was washed with saturated aqueousNaHCO₃ (50 mL), saturated aqueous NH₄Cl (50 mL), and brine,respectively, and dried with anhydrous Na₂SO₄. The solvent was removedand the residue was dried in vacuo to give crude compound 113 (41.4 g),which was used for next step without further purification. LC-MS (ESI)m/z 478.1 (M+H)⁺.

Step d.

A mixture of crude compound 113 (41.4 g) and NH₄OAc (100 g, 1.30 mol) intoluene (300 mL) was stirred at 120° C. overnight. The reaction mixturewas concentrated and the residue was diluted with EyOAc (500 mL). Themixture was washed with water and dried with anhydrous Na2SO4. Thesolvent was removed and the residue was purified by silica gel columnchromatography (Petroleum ether/acetone=6/1 tot/1 (v/v)) to givecompound 114 (24 g, 61% yield; two steps from 112) as a yellow solid.LC-MS (ESI): m/z 458.1 (M+H)⁺.

Step e.

A mixture of compound 114 (3 g, 6.55 mmol), bis(pinacolato)diboron (1.83g, 7.2 mmol), and K₂CO₃ (1.67 g, 17.03 mmol) in 1,4-dioxane (100 mL) wasadded Pd(dppf)Cl₂.DCM (0.8 g, 0.98 mmol) under an atmosphere of N₂.After stirring at 80° C. overnight under an atmosphere of N₂, thereaction mixture was filtered through CELITE™ 545 and the filtered cakewas washed with EtOAc (100 mL×3). The filtrate was washed with brine anddried with anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (DCM/MeOH=50/1 (v/v)) togive compound 115 (2.0 g, 61% yield). LC-MS (ESI): m/z 506.3 (M+H)⁺.

Step f.

To a mixture of compound 111 (500 mg, 1.3 mmol), compound 115 (900 mg,1.78 mmol), and NaHCO₃ (328 mg, 3.9 mmol) in DME (15 mL) and water (5mL) was added Pd(dppf)Cl₂.DCM (106 mg, 0.13 mmol) under an atmosphere ofN₂. After stirring at 80° C. overnight under an atmosphere of N₂, thereaction mixture was concentrated and the residue was diluted with EtOAc(100 mL) and water (25 mL). The organic phase was washed with brined anddried with anhydrous Na₂SO₄. The solvent was removed and the residue wassilica gel column chromatography (Petroleum ether/acetone=4/1 (v/v)) togive compound 116 (310 mg, 35% yield) as a yellow solid. LC-MS (ESI):m/z 703.3 (M+Na)⁺.

Step g.

To a stirred solution of compound 116 (150 mg, 0.31 mmol) in dioxane(3.0 mL) was added 4 N HCl in dioxane (3.0 mL) at rt. After stirring atrt for 3 h, the reaction mixture was concentrated and the residue wasdried in vacuo to give an HCl salt, which was used for the next stepwithout further purification.

Step h.

Subsequently, the HCl salt was dissolved in DMF (3.0 mL) and theresulting mixture was added DIPEA (0.43 mL, 2.5 mmol), N-Moc-L-Val-OH(136 mg, 0.78 mmol), and HATU (353 mg, 0.93 mmol), respectively. Afterstirring at rt for 2 h, the reaction mixture was concentrated and theresidue was purified by preparative HPLC to give compound 117. LC-MS(ESI): m/z 795.4 (M+H)⁺.

Example 7 Synthesis of compounds of Formula IIIg

Step a.

Referring to Scheme 7-1, to a solution of 6-bromoquinolin-2(1H)-one (70)(0.40 g, 1.8 mmol) in anhydrous pyridine (12 mL) was added drop-wiselywith Tf₂O (0.81 g, 2.9 mmol) at 0° C. After stirring at 0° C. for 1 hand at rt for 3 h, the reaction mixture was concentrated. The residuewas dissolved in DCM (100 mL); the resulting mixture was washed withwater (25 mL×3) and dried with anhydrous Na2SO4. The solvent was removedand the residue was purified by silica gel column chromatography(Petroleum ether/acetone=2/1 (v/v)) to give compound 86 (0.54 g, 84%yield) as a yellow solid. LC-MS (ESI) m/z 355.9 (M+H)⁺.

Step b.

To a mixture of compound 86 (0.54 g, 1.5 mmol), (S)-tert-butyl2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.24 g, 3.0 mmol), and NaHCO₃ (1.01 g, 12.0 mmol) in1,2-dimethoxyethane (30 mL) and water (10 mL) was addedPd(dppf)Cl₂.CH₂Cl₂ (0.27 g, 0.3 mmol) at rt under an atmosphere of N₂.After stirring at 80° C. overnight, the reaction mixture wasconcentrated. The residue was diluted with EtOAc (100 mL) and water (25mL). The organic phase was isolated, washed with brine, and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was purifiedby silica gel column chromatography (Petroleum ether/EtOAc=1/1 (v/v)) togive compound 87 (1.0 g, 95% yield) as a yellow solid. LC-MS (ESI) m/z700.4 (M+H)⁺.

Step c.

To a solution of compound 87 (100 mg, 0.14 mmol) in dioxane (2 mL) wasadded 4N HCl in dioxane (2 mL) at rt. After stirring at rt for 4 h, thereaction mixture was concentrated and the residue was dried in vacuo togive an HCl salt, which was used directly for the next step withoutfurther purification. LC-MS (ESI) m/z 500.2 (M+H)⁺.

Step d.

Subsequently, the HCl salt was dissolved in DMF (2 mL) and the resultingmixture was added Et₃N (0.20 mL, 1.4 mmol), N-Moc-L-Val-OH (55 mg, 0.32mmol), and HATU (122 mg, 0.32 mmol), respectively. After stirring at rtfor 30 min, the reaction mixture was concentrated and the residue waspurified by preparative HPLC to give compound 88. LC-MS (ESI): m/z 814.3(M+H)⁺.

Step a.

Referring to Scheme 7-2, a mixture of compound 89 (7.44 g, 40.0 mmol)and Ethyl 2,2-diethoxyacetate (9.15 g, 52.0 mmol) was stirred at 130° C.for 7 h. The reaction mixture was dissolved in petroleum ether (250 mL).The resulting mixture was washed with sat. aq. NH₄Cl and brine,respectively, and dried with anhydrous Na₂SO₄. The solvent was removedand the residue was dried in vacuo to give crude compound 90 (11.4 g) asa yellow oil, which was used for the next step without furtherpurification. LC-MS (ESI) m/z 316.0 (M+H)⁺.

Step b.

A mixture of compound 90 (12.4 g, 40 mmol) in conc. H₂SO₄ (50 mL) wasstirred at rt for 5 h. Subsequently, the reaction mixture was pouredinto ice-water. The suspension was filtered and the filtrate wasneutralized with 10% NH₄OH. The solid was collected by filtration,washed with water, and dried in vacuo to give a mixture of compounds 91and 91′. LCMS (ESI) m/z 224.0 (M+H)⁺.

Step c.

A mixture of compounds 92 and 92′ (222 mg, 1.0 mmol) in anhydrousPyridine (5 mL) was added Tf₂O (0.5 mL) at 0° C. After stirring at rtfor 8 h, the reaction mixture was concentrated and the residue wasdissolved in DCM (50 mL). The mixture was washed with water (25 mL×3)and dried with anhydrous Na₂SO₄. The solvent was removed and the residuewas purified with silica gel column chromatography (EtOAc/Petroleumether=5/1 (v/v)) to give a mixture of compounds 92 and 92′ (160 mg, 45%yield) as a yellow oil. LC-MS (ESI) m/z 355.9 (M+H)⁺.

Step d.

To a mixture of compounds 92 and 92′ (160 mg, 0.45 mmol), (S)-tert-butyl2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(463 mg, 1.12 mmol), and NaHCO₃ (227 mg, 2.7 mmol) in1,2-dimethoxyethane (30 mL) and water (10 mL) was addedPd(dppf)Cl₂.CH₂Cl₂ (80 mg, 0.09 mmol) at rt under an atmosphere of N₂.After stirring at 80° C. overnight, the reaction mixture wasconcentrated and the residue was added EtOAc (100 mL) and water (20 mL).The organic phase was isolated, washed with brine, and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was purifiedby silica gel column chromatography (Petroleum ether/EtOAc=1/1 (v/v)) togive compound 93 (180 mg, 57% yield) and compound 93′ (60 mg, 19%yield). LC-MS (ESI) m/z 700.4 (M+H)⁺.

Step e.

To a solution of compound 93 (100 mg, 0.14 mmol) in dioxane (2 mL) wasadded 4N HCl in dioxane (2 mL). After stirring at rt for 3 h, thereaction mixture was concentrated and the residue was dried in vacuo togive an HCl salt, which was used for the next step without furtherpurification. LC-MS (ESI) m/z 500.2 (M+H)⁺.

Step f.

Subsequently, the HCl salt was dissolved in DMF (2 mL) and the mixturewas added Et₃N (0.2 mL, 1.4 mmol), N-Moc-L-Val-OH (55 mg, 0.32 mmol),and HATU (122 mg, 0.32 mmol), respectively. After stirring at rt for 1hr, the reaction mixture was concentrated and the residue was purifiedby preparative HPLC to give compound 94. LC-MS (ESI): m/z 814.4 (M+H)⁺.

Example 8 Synthesis of compounds of Formula IIg

Step a.

Referring to Scheme 8-1, to a solution of compound 118 (57.5 g, 290mmol) in HOAc (100 mL) was slowly added Br₂ (49.0 g, 290 mmol) at rt.After stirring at rt for 2 h, the reaction mixture was slowly addedsaturated aqueous NaHCO₃. The organic phase was washed with brine anddried with anhydrous Na₂SO₄. The solvent was removed and the residue wasdried in vacuo to give crude compound 119 (60 g), which was used fornext step without further purification. LC-MS (ESI): m/z 276.9 (M+H)⁺.

Step b.

To a solution of compound 119 (25.0 g, 89.9 mmol) in CH₃CN (100 mL) wasadded (S)—N-Boc-Pro-OH (19.4 g, 89.9 mmol), followed by Et₃N (37.35 mL,269.7 mmol) at rt. After stirring at rt for 2 h, the reaction mixturewas concentrated and the residue was diluted with DCM (250 mL). Themixture was washed with water and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was dried in vacuo to give compound120 (37 g), which was used for the next step without furtherpurification. LC-MS (ESI): m/z 313.2 (M−100+H)⁺.

Step c.

A mixture of crude compound 120 (37 g) and NH₄OAc (69.2 g, 899 mol) inxylene (100 mL) was stirred at 140° C. overnight. The reaction mixturewas concentrated and the residue was diluted with DCM (500 mL). Themixture was washed with brine and dried with anhydrous Na2SO4. Thesolvent was removed and the residue was purified by silica gel columnchromatography (Petroleum ether/acetone=10/1 (v/v)) to give compound 121(12 g, 40% yield; three steps from compound 119) as a white solid. LC-MS(ESI): m/z 392.1 (M+H)⁺.

Step d.

To a mixture of compound 121 (3 g, 7.65 mmol), bis(pinacolato)diboron(4.24 g, 16.8 mmol), KOAc (1.87 g, 19.1 mmol) in 1,4-dioxane (200 mL)was added Pd(dppf)Cl₂ (624 mg, 0.765 mmol) under an atmosphere of N₂.After stirring at 80° C. overnight under an atmosphere of N2, thereaction mixture was filtered through CELITE™ 545 and the filtered cakewas washed with EtOAc (100 mL×3). The filtrate was washed with brine anddried with anhydrous Na₂SO₄. The solvent was removed and the residue waspurified with silica gel column chromatography (Petroleumether/acetone=8/1 (v/v)) to give compound 122 (2.9 g, 86% yield) as agray solid. LC-MS (ESI) m/z 440.3 (M+H)⁺.

Step e.

To a boiling solution of 2-naphthoic acid (123) (50.0 g, 290 mmol) inHOAc (100 mL) was slowly added a mixture of Br₂ (46.3 g, 290 mmol) andI₂ (1.25 g, 43.5 mmol). After completing the addition, the reactionmixture was refluxed for 30 min. The reaction mixture was cooled to rtand filtered. The solid was washed with HOAc and dried in vacuo to givecrude compound 124 (50 g), which was used for the next step withoutfurther purification. LC-MS (ESI): m/z 251.0 (M+H)⁺.

Step f.

A mixture of compound 124 (10.0 g, 39.8 mmol) in CH₃CN (200 mL) wasadded EDCI (18.3 g, 95.5 mmol), Et₃N (16.08 mL, 159.2 mmol), andN,O-Dimethylhydroxylamine hydrochloride (4.8 g, 50 mmol) at rt. Afterstirring at rt overnight, the reaction mixture was concentrated and theresidue was diluted with DCM (250 mL). The mixture was washed withsaturated aqueous NH₄Cl, saturated aqueous NaHCO₃, and brine,respectively and dried with anhydrous Na₂SO₄. The solvent was removedand the residue was purified by silica gel column chromatography(Petroleum ether/EtOAc=8/1 (v/v)) to give compound 125 (3.6 g, 31%yield) as a white solid. LC-MS (ESI): m/z 294.0 (M+H)⁺.

Step g.

To a solution of compound 125 (3.60 g, 12.2 mmol) in THF (150 mL) wasslowly added 3M MeMgCl in THF (8.31 mL) at 0° C. After stirring at 0° C.for 1 h and at rt for 1 h, the reaction was quenched by adding saturatedaqueous NH₄Cl (5 mL). The solvent was removed and the residue wasdiluted with DCM. The mixture was washed with water and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was purifiedby silica gel column chromatography (Petroleum ether/AcOEt=10/1 (v/v))to give compound 126 (3.05 g, 100% yield) as a white solid. LC-MS (ESI):m/z 249.0 (M+H)⁺.

Step h.

To a solution of compound 126 (3.05 g, 12.2 mmol) in DCM (100 mL) wasslowly added Br₂ (1.93 g, 12.2 mmol) in DCM (10 mL) at rt. Afterstirring at rt for 2 h, the reaction was quenched by adding saturatedaqueous NaHCO3 (10 mL). The organic layer was washed with brine anddried with anhydrous Na₂SO₄. The solvent was removed and the residue wasdried in vacuo to give crude compound 127 (4.0 g), which was used forthe next step without further purification. LC-MS (ESI): m/z 326.9(M+H)⁺.

Step i.

To a solution of crude compound 127 (4.0 g) in CH₃CN (15 mL) was added(S)—N-Boc-Pro-OH (3.14 g, 14.6 mmol) and Et₃N (3.70 g, 36.6 mmol). Afterstirring at rt for 2 h, the reaction mixture was concentrated and theresidue was diluted with DCM (200 mL). Subsequently, the mixture waswashed with saturated aqueous NH₄Cl and water respective, and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give crude compound 128 (5.6 g), which was used for the nextstep without further purification. LC-MS (EST): m/z 462.1 (M+H)⁺.

Step j.

A mixture of crude compound 128 (5.6 g) and NH₄OAc (9.36 g, 122 mmol) intoluene (80 mL) was stirred at 110° C. overnight. The reaction mixturewas concentrated and the residue was diluted with DCM (250 mL). Themixture was washed with water and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (Petroleum ether/EtOAc=5/1 (v/v)) to give compound 129(3.0 g, 56 yield) as a white solid. LC-MS (ESI): m/z 442.1 (M+H)⁺.

Step k.

To a mixture of compound 122 (633 mg, 1.44 mmol), compound 129 (500 mg,1.31 mmol), and NaHCO₃ (330 mg, 3.01 mmol) in 1,2-dimethoxyethane (15mL) and water (5 mL) was added Pd(dppf)Cl₂ (107 mg, 0.131 mmol) under anatmosphere of N₂. After stirring at 80° C. overnight, the reactionmixture was concentrated and the residue was diluted with EtOAc (50 mL)and water (20 mL). The organic phase was washed with brine and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleum ether/EtOAc=10/1(v/v)) to give compound 130 (400 mg, 45% yield) as a yellow solid. LC-MS(ESI): m/z 675.4 (M+H)⁺.

Step l.

To a solution of compound 130 (150 mg, 0.22 mmol) in dioxane (2.0 mL)was added 4N HCl in dioxane (2.0 mL) at rt. After stirring at rt for 3h, the reaction mixture was concentrated and the residue was dried invacuo to give an HCl salt, which was used for the next step withoutfurther purification. LC-MS (ESI): m/z 475.3 (M+H)⁺.

Step m.

Subsequently, the HCl salt was dissolved in DMF (2.0 mL) and the mixturewas added DIPEA (0.36 mL, 2.2 mmol), N-Moc-L-Val-OH (86 mg, 0.49 mmol),and HATU (202 mg, 0.49 mmol) at rt. After stirring at rt for 1 h, thereaction mixture was concentrated and the residue was purified bypreparative HPLC to give compound 131. LC-MS (ESI): m/z 789.4 (M+H)⁺.

Example 9 Synthesis of compounds of Formula IVa

Step a.

Referring to Scheme 9-1, a mixture of 2-bromobenzothiazole 1 (2.72 g,9.5 mmol), 4-methoxycarbonylphenylboronic acid (2) (1.80 g, 10 mmol),Pd(dppf)Cl₂ (388 mg, 0.475 mmol) in 2 M Na₂CO₃ (10 mL) and dioxane (20mL) was treated by a repeated process ofdegas-and-refilled-with-nitrogen three times. The reaction mixture wasthen stirred at 95° C. in nitrogen atmosphere for 4 h. After beingcooled, the mixture was diluted with THF, and then filtered through apad of CELITE™ 545. The filtrate was concentrated and the crude productwas directly purified by flash chromatography (using methylene chlorideas eluent) to give compound 3 (1.96 g, 60% yield) as a white solid.

Step b.

A solution of n-butyllithium (2.5 M in hexane, 25.3 mL, 63.1 mmol) wasslowly added into a solution of diisopropylamine (6.97 g, 68.8 mmol) inTHF (20 mL) at −78° C. over 15 min. After addition, the solution wasallowed to stir for 30 min at −78° C. and then warm up to 0° C. The LDAsolution was cooled to −78° C. for next step.

Step c.

A solution of 3 (1.96 g, 5.74 mmol) and chloroiodomethane (7.30 g, 41.2mmol) in THF (15 mL) was cooled to −78° C. The LDA solution preparedabove was slowly cannulated into this solution over 20 min. Theresulting mixture was stirred for additional 1 h. The reaction wasquenched by slowly adding a solution of acetic acid in THF (1/1 (v/v),40 mL) at −78° C. The reaction mixture was warmed up to rt and thendiluted with water and ethyl acetate. The aqueous layer was extractedwith ethyl acetate. A combined organic layer was dried over anhydroussodium sulfate, filtered and concentrated. The crude product 4 (1.80 g)was dried in vacuoand the residue was used directly for nextcondensation reaction.

Step d.

A mixture of 4 (0.59 g, 1.61 mmol), N-Boc-L-Proline (0.83 g, 3.85 mmol),KI (0.64 g, 3.85 mmol) and diisopropylethylamine (0.64 g, 3.85 mmol) inDMF (40 mL) was stirred at 50° C. for 4 h. The solvent was evaporatedand the residue was treated with water. The solid was collected byfiltration and washed with water twice. After being dried in vacuum, thecrude product was purified by flash chromatography (ethylacetate/hexanes=1/9 to 1/5 (v/v)) to afford 5 (0.92 g, 67% yield) as awhite solid.

Step e.

A mixture of diester 5 (0.81 g, 1.12 mmol), ammonium acetate (2.59 g,33.5 mmol) and triethylamine (3.39 g, 33.5 mmol) in toluene (100 mL) ina sealed tube was stirred at 140° C. for 90 min. After being cooled, thereaction mixture was transferred into a flask and concentrated todryness. The residue was partitioned between chloroform and water, andthe organic layer was washed with water and brine, and concentrated. Thecrude product was purified by flash chromatography (NH₄OH/acetone/ethylacetate=112/100 (v/v/v)) to give compound 6 (0.51 g, 67% yield) as awhite solid.

Step f. Trifluoroacetic acid (3 mL) was slowly added into a solution of6 in methylene chloride (10 mL) at rt. The resulting mixture was stirredat the temperature for 1 h, and concentrated to dryness. The residue wasdissolved in water, and the aqueous solution was basified to pH 11. Theproduct was extracted with chloroform 5 times. After removal of thesolvent, 7 (274 mg, 76%) was obtained as its TFA salt.

Step g.

A mixture of N-methoxycarbonyl-L-valine (40 mg, 0.23 mmol), DIPEA (98mg, 0.76 mmol) and HATU (87 mg, 0.23 mmol) in DMF was stirred at rt for30 min. 7 (80 mg, 0.076 mmol) was added as solid. The reaction mixturewas stirred at rt for 2 h, and then dropped into water. The precipitatewas formed and collected by filtration. The crude product was purifiedby prep HPLC to afford compound 8 (16 mg). ¹H NMR (CDCl₃, 300 MHz) δ7.8-7.6 (4H, m), 7.5-7.3 (3H, m), 7.08 (2H, s), 5.5-5.4 (2H, d), 5.3-5.2(2H, m), 5.05 (1H, s), 4.5-4.3 (2H, m), 4.2-4.1 (1H, m), 3.8-4.0 (4H,m), 3.74 (6H, s), 2.6-2.0 (10H, m), 1.10 (6H, d), 1.95 (6H, d) ppm.LC-MS (EST): m/z 796.4 (M+H)⁺.

Step a.

Referring to Scheme 9-2, to a mixture of compound 2 (6.31 g, 35 mmol)and HATU (14.63 g, 38.5 mmol,) in CH₃CN (150 mL) was added slowly DIEPA(9.05 g, 11.35 mL, 70 mmol). The resulting mixture was stirred at rt for15 min. To the mixture was added 3,4-diamino-benzoic acid ethyl ester 1(6.31 g, 35 mmol) at rt, and stir continued at rt for 17 h. The reactionwas quenched with saturated NaHCO₃ solution, and extracted with EtOAc.(3×150 mL). Combined organic phases were washed with H₂O (2×200 mL) andbrine (200 mL), dried over Na₂SO₄, filtered and concentrated on a rotaryevaporator. The crude mixture was purified by column chromatographyeluting hexane/EtOAc=3/1 to 2/1 (v/v) to give an amide (11.2 g, 94%) asyellow-brown solid. LC-MS (ESI): m/z (M+H)⁺: 343, (M−H)⁻: 341.

Step b.

A mixture of the product (11.2 g, 33 mmol) from above reaction in AcOH(100 mL) was heated at 40° C. for 18 h. The temperature was allowed towarm to 60° C., and further heated the mixture for 24 h. All startingmaterial was consumed based on LC-MS analysis. The excess solvent wasremoved on a rotary evaporator to give a crude mixture, which wassubject to purification by column chromatography eluting withhexane/EtOAc=3/1 (v/v) to give a functionalized benzimidazole (10.2 g,96% yield). LC-MS (ESI): m/z 325.1 (M+H)⁺.

Step c.

A mixture of the product (10.2 g, 31 mmol) from the above reaction andLiOH (7.54 g, 0.31 mol) in MeOH (200 mL) was heated under refluxcondition for 60 h. The milky mixture was acidified with 10% HClsolution to adjust the pH 1 to give white precipitates. The precipitatewas collected by filtration and then dried in vacuo to afford compound 3(8.9 g, quantitative yield), which was used for the next step withoutfurther purification. LC-MS (ESI): m/z 283.1 (M+H)⁺.

Step d.

A mixture of 3 (8.9 g, 31 mmol) in thionyl chloride (60 mL) was refluxedfor 3 h. The reaction mixture was concentrated and the residue was driedin vacuo to give acid chloride, which was mL suspended in a mixture ofdried diethyl ether (200 mL)/THF (50 mL). To the suspension was addeddropwise a flash generated diazomethane solution (approximately 166 mmolof diazomethane solution generated from 251 mmol of4-N,N-trimethyl-benzenesulfonamide) at 0° C., and then stirred it at 0°C. to rt overnight (20 h). All volatile was removed on a rotaryevaporator to give a residue. The residue was purified by columnchromatography eluting hexanes/EtOAc=3/1 (v/v) to give a yellow solid(1.89 g, 17% yield).

Step e.

To a mixture of2-diazo-1-{2-[4-(2-diazo-acetyl)-phenyl]-1-methyl-1H-benzoimidazol-5-yl}-ethanoneobtained from above (1.89 g, 5.49 mmol) in AcOH (50 mL) was added slowlyHBr (48% in AcoH, 1.62 mL, 14.31 mmol) at rt. The resulting mixture wasstirred at rt for 13 h, and then all volatile was removed on a rotaryevaporator to give crude mixture. The crude mixture was further driedwith toluene on a rotary evaporator (2×25 mL) to give compound 4 asyellow solid, which was used for the next step without furtherpurification. LC-MS (ESI): m/z 448.9 (M+H)⁺.

Step f.

To a crude mixture of compound 4 (˜5.49 mmol) in CH₃CN (50 mL) was addedN-Boc-L-Proline (2.59 g, 12.01 mmol), followed by adding DIEPA (3.71 mL,22.9 mmol) at rt. The resulting mixture was stirred at rt for 5 h, andquenched with H₂O. The mixture was extracted with EtOAc (3×50 mL). Thecombined organic phases were washed with H₂O (50 mL) and brined (50 mL),dried over Na₂SO₄, filtered, and concentrated on a rotary evaporator.The crude mixture was used for the next step without furtherpurification. LC-MS (ESI): m/z 719.3 (M+H)⁺.

Step g.

To a crude solution of 5 (˜5.72 mmol) in xylene (50 mL) was added NH₄OAc(6.61 g, 85.8 mmol). The resulting mixture was heated at 145° C. for 1.5h, and then all solvent was removed on a rotary evaporator to give acrude mixture, which was subject to column chromatography eluting withhexane:EtOAc=1:3 to EtOAc only. Yellow-brown solid was obtained ascompound 6 (717 mg). LC-MS (ESI): m/z 679.4 (M+H)⁺.

Step h.

To a crude solution of 6 (717 mg, 1.06 mmol) in THF (7.5 mL) was addedHCl (4.0 M in dioxane, 10 mL) at rt. The resulting mixture was stirredat rt for 16 h, and then all volatile was removed on a rotary evaporatorto give yellow solid. The yellow solid was washed with diethyl ether(2×10 mL) and then further dried on in vacuo to give an HCL salt, whichwas used for the next step without further purification. LC-MS (ESI):m/z 479.3. ¹H NMR spectrum showed the crude product was a mixture of tworegioisomers with a ratio of 1:1. (M+H)⁺.

Step i.

To a crude solution of the HCl salt (48 mg, ˜0.1 mmol), N-Boc-L-Val-OH(35 mg, 0.2 mmol), and HATU (76 mg, 0.2 mmol) in CH₃CN (1.0 mL) wasadded DTEPA (65 μL, 0.4 mmol). The resulting mixture was stirred at rtfor 2.5 h, and then all solvent was removed on a rotary evaporator togive crude mixture. The crude mixture was purified by prep-HPLC elutingH₂O to CH₃CN. Two regioisomers were obtained as 10.0 mg (yellow solid,7) and 8.7 mg (yellow solid, 7′), respectively. Characterization of 7:¹H NMR (300 MHz, CDCl₃) δ 8.32 (br s, 1H), 7.19-7.92 (m, 8H), 5.39-5.86(m, 2H), 5.21-5.34 (m, 2H), 4.30-4.42 (m, 2H), 3.60-3.78 (m, 12H), 2.76(Br s, 1H), 2.20-2.44 (m, 4H), 1.98-2.18 (m, 4H), 0.89-1.12 (m, 12H)ppm. LC-MS (ESI): m/z (M+2)/2⁺: 397, (M+1)⁺: 794.

Characterization of compound 7′. ¹H NMR (300 MHz, CDCl₃) δ 8.30 (Br s,1H), 7.10-7.84 (m, 8H), 5.44-5.64 (m, 2H), 5.22-5.32 (m, 2H), 4.39 (t,J=6.6 Hz, 2H), 3.63-4.00 (m, 12H), 2.68 (br s, 1H), 2.21-2.38 (m, 4H),2.00-2.16 (m, 4H), 0.87-1.07 (m, 12H). LC-MS (ESI): m/z 793.4 (M+H)⁺.

The N-Moc-D-Phg-OHcapped analog 8 were obtained by following the sameprocedure as that used for synthesizing compounds 7 and 7′ and usingN-Moc-D-Phg-OH instead of N-Moc-L-Val-OH as an amide reagent. ¹H NMR(300 MHz, CDCl₃) δ 8.32 (br s, 1H), 7.23-8.00 (m, 18H), 5.42-5.60 (m,2H), 5.24-5.40 (m, 2H), 3.86 (br s, 4H), 3.56-3.74 (m, 6H), 2.64-2.86(m, 2H), 2.00-2.36 (m, 4H), 1.91 (br s, 2H) ppm. LC-MS (ESI): m/z(M+2)/2⁺: 431, (M+1)⁺: 860.

Step a

A mixture of methyl 3-amino-4-hydroxybenzoate (2.5 g, 15 mmol) andmethyl 4-formylbenzoate (2.46 g, 15 mmol) in methanol (75 mL) wasstirred at rt overnight. The solvent was evaporated under reducedpressure and the remaining residue was dissolved in dichloromethane (150mL). DDQ (3.5 g, 15.4 mmol) was added and the reaction mixture wasstirred at rt for 1 h. Saturated NaHCO₃ (200 mL) was added. Thesuspension was filtered off, the resulting solid was washed withsaturated NaHCO₃ (50 mL), water (50 mL), and ethyl acetate (100 mL) anddried in vacuo to give compound 1 (4 g, 86% yield) as yellow solid.

Step b.

A mixture of diester 1 (4 g, 12.8 mmol) and lithium hydroxidemonohydrate (2.7 g, 64 mmol) in a solvent mixture of methanol and water(60 mL, methanol/water=1/5) was refluxed for 6 h. Methanol wasevaporated and the remaining aqueous solution was neutralized by HCl(con). The resulting suspension solution was filtered off, the solid waswashed with water (50 mL) and dried in vacuo to give the correspondingdicarboxylic acid (3.3 g, 95% yield) as yellow solid.

Step c.

A sample of the dicarboxylic acid (2.88 g, 10.2 mmol) was suspended inthionyl chloride (30 mL), the mixture refluxed for 6 h. The reactionmixture was evaporated under reduced pressure and dried in vacuo toprovide the corresponding diacyl chloride (3.25 g) as yellow solid.

Step d.

A suspension of the diacyl chloride obtained (1.5 g, 4.7 mmol) in etherwas treated with diazomethane (71 mL, 0.33 N in ether, 23 mmol) at 0° C.for 2 h. The solvent was evaporated under reduced pressure and dried invacuo to give the corresponding diazoketone (1.55 g) as yellow solid.LC-MS (ESI): m/z 332.1 [M+H]^(|).

Step e.

The diazoketone obtained (1.55 g, 4.7 mmol) was suspended in acetic acid(10 mL) and the mixture was drop-wisely added 48% HBr in AcOH (3.93 g,23.3 mmol) at 0° C. The reaction mixture was then warmed up to rt andstirred for 1 h. Saturated Na₂CO₃ was added slowly into the reactionmixture to neutralize the acid. The resulting suspension solution wasfiltered off and the solid was washed with water and dried in vacuo togive bromoketone 2 (1.38 g, 69% yield) as yellow solid.

Step f.

A solution of bromoketone 2 (1.38 g, 3.2 mmol), N-Boc-LProline (2.7 g,12.6 mmol) and DIPEA (2.2 mL, 12.6 mmol) in acetonitrile (3 mL) wasstirred at rt overnight.

Acetonitrile was evaporated and the remaining residue was partitionedbetween ethyl acetate (50 mL) and water (25 mL). The organic phase wasthen collected and dried over Na₂SO₄. After concentration under reducedpressure, the crude product was purified over silica gel (ethylacetate/hexane=35/65) to give ester 3 (0.56 g, 25% yield) as yellowsolid. LC-MS (ESI): m/z 706.3 [M+H]⁺.

Step g.

A mixture of ester 3 (560 mg, 0.8 mmol) and ammonium acetate (1.84 g, 24mmol) in degassed xylem (3.3 mL) in a scaled parr bottle was stirred at140° C. for 90 min. Upon removal of volatile solvents the residualmaterial was purified by silica gel chromotagraphy (ethyl acetate 100%,then ethyl acetate/methanol=90/10 (v/v)) to give bisimidazole 4 (474 mg,89% yield) as yellow solid. LC-MS (ESI): m/z 666.3 [M+H]⁺.

Step h.

To a solution of bisimidazole 4 (474 mg, 0.71 mmol) in THF (20 mL) wasadded 4N HCl in dioxane (3.6 mL, 14 mmol) at rt. The reaction mixturewas stirred at rt for 2 h. The solvent was evaporated and the residuewas dried in vacuo to give 5 (ca. 330 mg) as yellow HCL salt, which wasused for the next step without further purification. LC-MS (ESI): m/z465.2 [M+H]⁺.

Step i.

To a solution of 5 (135 mg, 0.29 mmol), N-Moc_L-Val-OH (152.6 mg, 0.87mmol) and DMTMM (240.5 mg, 0.87 mmol) in a solvent mixture of DMF-THF (2mL, DMF/THF=1/3 (v/v)) was added DIPEA (0.5 mL, 2.9 mmol) at rt. Thereaction mixture was stirred at rt for 2 h. THF was evaporated and theremaining reaction mixture was purified via prep-HPLC to providecompound 6 as white solid. ¹H NMR (300 MHz, CD₃OD) δ 0.92 (m, 12H), 2.05(m, 4H). 2.26 (m, 4H), 3.65 (s, 6H), 3.9 (m, 2H), 3.99 (m, 2H), 4.22 (m,2H), 5.18 (m, 2H), 7.33 (s, 1H), 7.48 (s, 1H), 7.64 (d, J=8.7 Hz, 1H),7.73 (d, J=8.1 Hz, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.99 (s, 1H), 8.21 (d,J=8.7 Hz, 2H) ppm. LC-MS (ESI): m/z 780.4 (M+H)⁺.

Step a.

Referring to Scheme 9-4, ethyl 2-bromo-6-benothiazolecarboxylate (100mg, 0.35 mmol), 4-acetylphenylboronic acid (69 mg, 0.42 mmol),Pd(dppf)Cl₂ (14 mg, 0.05 mmol) and Cs₂CO₃ (228 mg, 0.70 mmol) weredissolved in a mixed solvent (THF/DMF=3:2, 5 mL) in a Schlenk flask. Thereaction mixture was degassed and refilled with nitrogen three times.The flask was heated to 95° C. under nitrogen 6 h, cooled to rt. Thesolvent was removed under reduced pressure and the residue wasre-dissolved in dichloromethane (DCM). The DCM solution was washed withsaturated NaHCO₃, brine and dried with Na₂SO₄, concentrated, purified bysilica gel column (DCM/MeOH=9.8/0.2 (v/v)) to give 1 as slight yellowsolid (70 mg, 62% yield). ¹H NMR (300 MHz, CDCl₃) δ 8.65 (s, 1H),8.17-8.21 (m, 3H), 8.06-8.13 (m, 3H), 4.43 (q, 2H), 2.66 (s, 3H), 1.44(t, 3H) ppm. LC-MS (ESI): m/z 326.1 (M+H)^(|).

Step b.

To a suspension of 1 (4.0 g, 12.3 mmol) in the solvent mixture ofTHF/MeOH/H₂O (100 mL) was added LiOH.H₂O (2.58 g, 61.5 mmol). Thereaction mixture was stirred at rt overnight. The volatile was removed,and water (50 mL) was added and the pH was adjusted to 1-2 with 2N HCl.The precipitate was filtered and dried to give a free acid (3.6 g, 100%)as white solid. LC-MS (ESI) m/z: 298.0 (M+H)^(|).

Step c.

A sample of the acid (3 g, 10 mmol) was suspended in thionyl chloride(50 mL), heated to refluxing for 2 h. The volatile was removed underreduced pressure and the residue (3.2 g) was dried in vacuo to give thecorresponding acyl chloride.

Step d.

To the suspension of the acyl chloride above (3 g, 9.5 mmol) in themixed solvent of DCM/THF (7/3 (v/v), 100 mL) at 0° C. was addedfresh-made diazomethane (5.0 equiv.) in diethyl ether. The reactionmixture was stirred from 0° C. to rt 1 h. LC-MS and ¹H NMR showedreaction was completed. The solvent was removed to give crude productdiazoketone. ¹H NMR (300 MHz, CDCl₃) δ 8.43 (s, 1H), 8.20-8.23 (d,J=7.5, 2H), 8.08-8.15 (m, 3H), 7.86 (d, J=7.8, 1H), 6.0 (s, 1H), 2.68(s, 3H) ppm.

Step e.

The dizoketone was dissolved in acetic acid (50 mL) and HBr (1.1 equiv,48% aq. solution) was added, stirred at rt for 1 h, concentrated to givecompound 2 (4.5 g).

Step f.

To a solution of the N-Cbz_L-Proline (3.59 g, 14.4 mmol) in acetonitrile(100 mL) and DMF (50 mL) was added diisopropylethylamine (6.0 mL, 36mmol) and 2 (4.5 g, 12 mmol) in acetonitrile (50 mL). The reactionmixture was stirred at rt overnight. The solvent was removed and productwas extracted with dichloromethane (3×), washed with NaHCO₃ (200 mL) andbrine, dried over Na₂SO₄. After removal of the solvent, the crudeproduct was purified on silica column (Hexane/EtOAc=1/1 (v/v)) to give 3(1.2 g). LC-MS (ESI): m/z 543.2 (M+H)⁺.

Step g.

To a solution of 3 (1.2 g, 2.2 mmol) and TEA (2.18 mL, 13.2 mmol) in DCMwas added TMS-OTf (0.8 mL, 4.4 mmol) at −78° C. After the reaction wasstirred to r.t overnight, PTT (910 mg, 2.42 mmol) was added. Thereaction was stirred at rt for 2 h and quenched with NaHCO₃ solution.The mixture was partitioned between water and CH₂Cl₂ (3×), and theorganic phase was washed with brine, dried, filtered and concentrated invacuo to give crude compound 4 (1.37 g).

Step h.

To a solution of N-Boc-L-Proline (568 mg, 2.6 mmol) in acetonitrile (10mL) was added DIPEA (0.54 mL, 3.3 mmol) and 4 (1.37 g, 2.2 mmol) inacetonitrile (10 mL). The reaction mixture was stirred at rt overnight.The solvent was removed and product was extracted with dichloromethane(3×), washed with NaHCO₃ (200 mL) and brine, dried with Na₂SO₄. Afterremoval of the solvent, the crude product was purified on silica column(Hexanes/EtOAc=1/1 (v/v)) to give 5 (900 mg, 54% yield). LC-MS (ESI):m/z 756.3 (M+H)⁺.

Step i.

To a solution of 5 (900 mg, 1.19 mmol) in o-xylene (20 mL) in a pressuretube was added ammonium acetate (2.75 g, 35.7 mmol) and triethylamine (5mL, 35.7 mmol). The tube was sealed and heated to 140° C. for 1.5 h,cooled to rt The volatile component was removed in vacuum, and theresidue was partitioned between water and CH₂Cl₂, and the organic phasewas dried, filtered and concentrated in vacuum. The resulting crudematerial was purified by a flash chromatography (Hex: EA: MeOH=5:5:1) toprovide 6 as yellow residue (630 mg, 74% yield). LC-MS (ESI): m/z 716.3(M+H)⁺.

Step j.

To a solution of 6 (630 mg, 0.88 mmol) in DCM (20 mL) was added TFA (5mL). The reaction mixture was stirred at rt for 2 h; TFA was removed togive a TFA salt, which was used for the next step without furtherpurification.

Step k.

To a solution of the TFA salt (550 mg, 0.88 mmol) in DMF (10 mL) wasadded N-Moc-L-Val-OH (308 mg, 1.76 mmol), HATU (502 mg, 1.32 mmol) andDIPEA (871) μL, 5.28 mmol). The reaction was stirred at rtrt overnight.The solvent was removed under reduced pressure. The crude product waspurified on silica gel column (CH₂Cl₂/MeOH=9.8/0.2 (v/v)) to give 7 (500mg, 74% yield). LC-MS (ESI): m/z 773.3 (M+H)⁺.

Step l. To a solution of 7 (500 mg, 0.647 mmol) in MeOH (20 mL) wasadded Pd/C (50 mg) and several drops of con. HCl, purged with H₂. Thereaction mixture was shaken in the shaker under 60 psi for 48 h. Themixture was filtered on CELITE™ and concentrated; the residue waspurified on silica gel column (DCM/MeOH=8/2 (v/v)) to give a free amine(300 mg).

Step m.

To a solution of the free amine from Step 8a (100 mg, 0.16 mmol) in DMF(5 mL) was added N-Moc-D-Phg-OH (43 mg, 0.204 mmol), HATU (60 mg, 0.157mmol) and DIPEA (155 μL, 0.942 mmol). The reaction was stirred at rtrtovernight. The solvent was removed under reduced pressure. The crudeproduct was purified on preparative HPLC to give 8 (33 mg), in which R″is a methyl group. LC-MS (ESI): m/z 830.3 (M+H)⁺.

Additional Examples

Similarly taking a sample of the free amine from Step 8a and bysubstituting N-Boc-D-Phg-OH for N-Moc-D-Phg-OH in Step b above, thecorresponding N-Boc analog 9 was obtained (75 mg). LC-MS (ESI) m/z:872.4 (M+H)]⁺.

Taking a sample of 9 (70 mg, 0.08 mmol) in DCM (15 mL) and treated withTFA (4 mL). The corresponding de-Boc product was obtained as a TFA salt.

To a solution of the TFA salt in THF (10 mL) was added DIPEA (132 μL,0.8 mmol) and CDI (39 mg, 0.24 mmol). The reaction was stirred at rtrtuntil the reaction completed (monitored by LC-MS). To the solution wasadded methyl amine hydrochloride (54 mg, 0.8 mmol). The reaction wasstirred at rtrt overnight. The solvent was removed and the residue waspurified by prep-HPLC to give compound 10 (12 mg) LC-MS (EST): m/z 829.4(M+H)⁺.

Example 10 Synthesis of compounds of Formula IIm

Step a.

Referring to Scheme 10-1, a mixture of methyl1,2,3,4-tetrahydroisoquinoline-6-carboxylate hydrochloride (4.28 g, 18.8mmol), 3,4,5-trifluorobenzoic acid methyl ester (3.8 g, 20 mmol) andK₂HPO₄ (17.0 g, 98 mmol) in 60 mL of DMSO was stirred at 80° C. for 8hours. After cooling down, the resulting mixture was partitioned in 800mL of EtOAc and 800 mL of H₂O. The organic layer was washed with H₂Ofollowed by brine and dried (Na₂SO₄). After concentration, the residuewas purified by silica gel column chromatography (hexanes/ethyl acetate(v/v), 3/1 to 1/1) to afford compound 1 (4.1 g, 60% yield) as slightlyyellow solid. ¹H NMR (300 MHz, CDCl₃) δ 7.80-7.88 (m, 2H), 7.48-7.62 (m,2H), 7.13 (d, 1H), 4.55 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.58 (t,2H), 3.04 (t, 2H) ppm.

Step b.

To a solution of 1 (2.0 g, 5.53 mmol) and chloroiodomethane (5.86 g,33.2 mmol) in THF (40 mL) was added LDA (precooled to −78° C., freshlymade from 10 mL diisoproylamine and 26.5 mL of 2.5 M n-BuLi in hexanesin 40 mL of THF) at −78° C. via cannula over 20 min. The reactionmixture was stirred for two hours at −78° C. before it was quenched bydropwise addition of 12 mL of AcOH/THF (v/v, 1/1). The resulting mixturewas warmed up and partitioned in EtOAc and saturated NaHCO₃. The organiclayer was washed with H₂O and dried over Na₂SO₄. After concentration,the residue was purified by the flash column chromatography (silica,hexanes/ethyl acetate, v/v, 4/1) to afford compound 2 (1.19 g, 54%yield) as brown solid. ¹H NMR (300 MHz, CDCl₃) δ 7.76-7.81 (m, 2H),7.42-7.56 (m, 2H), 7.20 (d, 1H), 4.69 (s, 2H), 4.61 (s, 2H), 4.57 (s,2H), 3.64 (t, 2H), 3.07 (t, 2H) ppm.

Step c.

Compound 2 (1.19 g, 2.99 mmol), N-Boc-L-Proline (1.65 g, 7.64 mmol), KI(1.27 g, 7.65 mmol) and DIPEA (1.32 mL, 7.63 mmol) were dissolved inCH₃CN (15.3 mL). The reaction mixture was then heated to 50° C. in anoil bath for 4 h and cooled to rt. The solvent was removed under vacuum,and the crude was partitioned in EtOAc (20 mL) and H₂O (10 mL). Theorganic layer was separated and the aqueous layer was extracted withEtOAc (2×20 mL). The combined EtOAc layers were dried over Na₂SO₄,filtered and concentrated under vacuum. The crude material was purifiedby flash column chromatograph eluted with hexanes/ethyl acetate (2/1 to1/1 (v/v)) to afford 3 as a yellow solid (1.1 g, 49% yield).

Step d.

Compound 3 (1.0 g, 1.32 mmol), NH₄OAc (2.89 g, 39.6 mmol), TEA (5.52 mL,96.6 mL) were dissolved in xylene (6.6 mL). The reaction mixture in asealed tube was then heated to 140° C. in an oil bath for 2 h and thencooled to rt. EtOAc and H₂O were added and the organic layer wasseparated. The aqueous layer was extracted with EtOAc (3×50 mL). Thecombined EtOAc layers were dried over Na₂SO₄, filtered and concentratedunder vacuum. The crude material was purified by flash columnchromatograph eluted with hexanes/ethyl acetate (1/2 to 0/1 (v/v)) toafford 4 as yellow solid (0.7 g, 74% yield).

Step 5.

A sample of compound 4 (0.50 g, 0.70 mmol), dissolved in dioxane (2 mL)with stirring, was treated with 4M HCl in dioxane (14.3 mL, 57.3 mmol).After stirring at rt for 2 h, the reaction mixture was concentrated andthe residue was dried in vacuo to give an HCl salt, which was used forthe next next without further purification.rt The HCl salt (50 mg, 0.097mmol) and N-Moc-L-Valine (34 mg, 0.194 mmol) were dissolved in DMF (2mL). DIPEA (0.2 mL, 1.16 mmol) and DMTMM (53.6 mg, 0.19 mmol) were addedto the mixture. After stirring at rt for overnight, the reaction mixturewas concentrated and the residue was purified by preparative HPLC togive rt compound 5 (9.3 mg) as a light yellow solid ¹H NMR (CD₃OD, 300MHz) δ 8.18 (1H, s), 7.52-6.99 (7H, m), 5.35-5.27 (1H, m), 5.19-5.11(2H, m), 4.33 (2H, s), 4.25-4.19 (2H, m), 4.03-3.95 (3H, m), 3.90-3.80(2H, m), 3.70-3.65 (6H, s), 3.50-3.45 (2H, m), 3.00-2.95 (2H, m),2.40-1.98 (12H, m), 0.99-0.88 (12H, m) ppm. LC-MS (ESI): m/z 830.4(M+H)⁺.

Example 11 Synthesis of compounds of Formula Vc

Step a.

Referring to Scheme 11-1, to a solution of the bromide 1 (2.0 g, 4.2mmol, prepared according to published conditions) in dioxane (60 mL) wasadded bis(pinacolato)diboron (4.32 g, 17 mmol), Pd(PPh₃)₄ (0.49 g, 0.42mmol) and potassium acetate (2.06 g, 21 mmol) under nitrogen atmosphere.The reaction mixture was stirred at 80° C. for 5 h, and then dilutedwith ethyl acetate (150 mL). The organic phase was washed with H₂O (20mL), dried over sodium sulfate and concentrated in vacuo. The residuewas further purified by silica gel column chromatography (haxanes/ethylacetate=1/4 to 0/1 (v/v)) to give 2 (1.73 g, 79% yield). LC-MS (ESI):m/z 523.3 (M+H)⁺.

Step b.

A mixture of 2-quinolinol triflate 3 (0.72 g, 1.4 mmol), boronic ester 2(0.73 g, 1.4 mmol), Pd(dppf)C₁₂-DCM (114 mg, 0.14 mmol) in 2 M Na₂CO₃(2.8 mL) and dioxane (5.6 mL) was treated by a process ofdegas-and-refilled-with-nitrogen three times. The reaction mixture wasthen stirred at 90° C. under nitrogen atmosphere for 4 h′ After beingcooled, the mixture was diluted with THF, and then filtered through apad of CELITE™. The filtrate was concentrated and the crude product waspurified by flash chromatography (NH₄OH/acetonitrile/ethyl acetate,1:8:100) affording a pure product 4 (0.80 g, 75% yield) as a whitesolid. LC-MS (ESI): m/z 759.4 (M+H)⁺.

Step c.

Trifluoroacetic acid (2.5 mL) was slowly added into a solution of 4(0.80 g, 1.5 mmol) in CH₂Cl₂ (5.0 mL) at rtrt. The resulting mixture wasstirred at rtrt for 2 h, and then concentrated to dryness. The crudeproduct was dried in vacuo to give a TFA salt, which was used for thenext step without further purification. LCMS (ESI): m/z 659.3 (M+H)^(|).

Step d.

To a mixture of the TFA salt (69.1 mg, 0.11 mmol) obtained from abovereaction in DMF (3 mL) was added DIPEA (0.23 mL, 1.4 mmol), followed byL-N-methoxycarbonyl-(4-tetrahydro-2H-pyran-4-yl)glycine (30 mg, 0.14mmol) and HATU (52 g, 0.14 mmol). After stirring at rt for 2 h, thereaction mixture was slowly dropped into H₂O while stirring. Theresulting precipitate was collected by filtration. The crude product waspurified by prep-HPLC to afford product 5 (34.5 mg). ¹H NMR (CDCl₃, 300MHz) δ 7.90 (m, 1H), 7.80-7.60 (m, 4H), 7.5 (m, 2H), 7.36 (d, 1H), 7.10(broad s, 2H), 7.56 (d, 1H), 7.44 (d, 1H), 5.28 (m, 2H), 4.54 (t, 1H),4.42 (t, 1H), 4.10-3.93 (m, 7H), 3.68 (m, 7H), 3.42 (m, 2H), 3.00-2.22(m, 8H), 2.08 (m, 5H), 1.80-1.40 (4H), 1.10-0.90 (m, 6H) ppm LC-MS(ESI): m/z 858.4 (M+H)^(|).

Step e.

A solution of compound 5 (37.7 mg, 0.044 mmol), DDQ (10.0 mg, 0.044mmol) in 6 mL of benzene was refluxed for 2.5 h. After removal of thesolvent, the crude product was purified by prep-HPLC to afford 6 (23 mg)as yellow powder. ¹H NMR (CDCl₃, 300 MHz) δ 8.40-7.40 (m, 10H), 7.22 (s,1H), 5.60-5.40 (m, 3H), 5.30 (m, 2H), 4.60-4.40 (m, 2H), 4.20-3.80 (m,6H), 3.70 (m, 7H), 3.44 (m, 3H), 2.50-2.00 (m, 13H), 1.10-0.92 (m, 6H)ppm. LC-MS (ESI): m/z 856.4 (M+H)⁺.

Following procedures and conditions described in Scheme 11-1 andsubstituting compound 1a for compound 1, compound 6a was prepared. ¹HNMR (300 MHz, CD₃OD) δ 9.21-9.18 (m, 1H), 8.79 (s, 1H), 8.56-8.50 (m,3H), 8.26-8.19 (m, 3H), 8.10-8.07 (m, 1H), 5.32-5.25 (m, 2H), 4.34-4.24(m, 2H), 4.13-4.06 (m, 2H), 3.95-3.89 (m, 4H), 3.67 (s, 6H), 3.24-3.09(m, 6H), 2.65-2.10 (m, 12H), 1.60-1.30 (m, 4H), 1.01-0.91 (m, 6H) ppm;LC-MS (ESI): m/z 872.4 (M+H)⁺.

Example 12 Additional Synthetic Schemes for Compounds of the Invention

Step a.

Referring to Scheme 12-8, a mixture of ethyl 4-bromo-2-methylbenzoate(1.0 g, 4.11 mmol) and NBS (1.15 g, 6.46 mmol) in CCl₄ (13.7 mL) washeated to reflux for 6 h. The white precipitate was filtered off and thefiltrate was concentrated under reduced pressure to obtain yellow oil 1(1.47 g) which contained approx. 25% of unreacted starting material byLC/MS. The crude material was used without further purification.

Step b.

Crude ester 1 (4.11 mmol) was dissolved in glacial acetic acid (13.7mL), and 4-bromoanaline (0.85 g, 4.93 mmol) was added to the solution.The reaction mixture was then heated to reflux for 12 h and cooled tort. H₂O (150 mL) was added and neutralized with solid Na₂CO₃ to pH 7.The aqueous solution was extracted with ethyl acetate (3×100 mL), andthe organic layers were dried over Na₂SO₄, filtered and concentratedunder vacuum. The crude material was purified by flash columnchromatograph eluted with hexanes/ethyl acetate (12/1 to 10/1) toremoved byproduct and then with pure ethyl acetate to afford brown solid2 (0.54 g, 36% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.79-7.69 (m, 3H),7.68-7.67 (m, 2H), 7.65-7.52 (m, 2H), 4.82 (m, 2H) ppm.

Step c.

A mixture of compound 2 (0.54 g, 1.46 mmol), pinacol diborane (0.82 g,3.22 mmol), KOAc (0.86 g 8.76 mmol), and Pd catalyst (0.12 g, 0.15 mmol)in dioxane (28 mL) was heated at 110° C. for 30 h. The reaction mixturewas cooled to rt and diluted with H₂O. The aqueous layer was extractedwith ethyl acetate, and the organic layer was dried over Na₂SO₄,filtered and concentrated under vacuum. The crude material was purifiedby flash column chromatograph eluted with ethyl acetate to afford darkyellow solid 3 (0.49 g, 73% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.90-7.70(m, 7H), 4.81 (s, 2H), 1.40-1.20 (m, 24H) ppm.

Step d.

A mixture of 3 (400 mg, 0.87 mmol), iodoimidazole compound 4 (630 mg,1.73 mmol) and Pd(PPh₃)₄ (200 mg, 0.17 mmol) and potassium carbonate(311 mg, 2.25 mmol) in DMSO (10 mL) and H₂O (3.5 mL) was heated at 100°C. for 14 h. The reaction mixture was cooled to rt and diluted with H₂Oand extracted with dichloromethane. The combine organic layers weredried over Na₂SO₄, filtered and concentrated under vacuum. The crudematerial was purified by flash column chromatography (ethylacetate/methanol=97/3 (v/v)) to afford 5 (357 mg, 61% yield) as a lightyellow solid. ¹H NMR (CDCl₃, 300 MHz) δ 7.95-6.90 (m, 9H), 4.95 (m, 2H),3.41 (m, 4H), 2.95 (m, 2H), 2.28-1.85 (m, 6H), 1.50 (s, 9H), 1.48 (s,9H) ppm.

Step e.

To a stirred suspension of 5 (40 mg, 0.059 mmol) in THF (0.6 mL) at rtwas added 4 N HCl solution in 1,4-dioxane (0.6 mL), and the mixture wasstirred at rt for 4 h. The reaction mixture was concentrated in vacuo togive an HCl salt (37 mg, 100% yield), which was used withoutpurification in the next step. LC-MS (ESI) m/z: [(M+2H)/2]⁺ 478.5.

Step f.

To a stirred solution of HCl salt from above (37 mg, 0.059 mmol) andN-methoxycarbonyl-L-valine (22.6 mg, 0.13 mmol) in DMF (2 mL) was addedHATU (49 mg, 0.13 mmol) followed by diisopropylethyl amine (0.1 mL, 0.59mmol). After being stirred at rt for 4 h, the reaction mixture wasdiluted with H₂O and extracted with dichloromethane. The combine organiclayers were dried over Na₂SO₄, filtered and concentrated under vacuum togive the crude product, which was purified by prep HPLC to give 6 (6.4mg, 14% yield) as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 7.95-7.20 (m,9H), 5.20 (m, 2H), 4.40-3.61 (m, 6H), 3.34 (s, 6H), 3.20-1.90 (m, 12H),0.95 (dd, 6H), 0.90 (dd, 6H). LC-MS (ESI) m/z: [M−H]⁻ 793.

Step g.

Similarly, the six-membered analogs (2a, 2b, 2c) of compound 2 wereprepared following published procedures. Compounds 2a, 2b and 2c werefurther transformed following the same synthetic sequences andconditions described above afford their perspective analogs of compound6.

Step a.

Referring to Scheme 12-9, to ethyl pyruvate (24.4 g, 23.4 mL, 210 mmol)was added dropwise H₂O₂ (35%, 13.6 g, 13.6 mL, 140 mmol) at 0° C.followed by stirring for 5 min. To a mixture of 6-bromo-benzothiazole(10.0 g, 46.7 mmol) in H₂O (45 mL) and H₂SO₄ (13.7 g, 7.5 mL, 140 mmol)was added simultaneously the fresh prepared ethyl pyruvate mixture andFeSO₄.7H₂O (38.9 g, 140 mmol) in H₂O (90 mL) at 0° C. The resultingmixture was kept at 0° C. and stirred at rt overnight. To the mixturewas added additional H₂SO₄ (27.4 g, 15.0 mL, 280 mmol) followed by freshprepared ethyl pyruvate mixture (28.8 g of ethyl pyruvate, 46.8 mL 420mmol and H₂O₂ 35%, 27.2 g, 27.2 mL, 280 mmol) and FeSO₄.7H₂O (77.8 g,280 mmol) in H₂O (180 mL) at 0° C. After stirring at 0° C. for 7.5 h,excess ice was added to the reaction mixture and the pH was adjusted to10-11 with a 2.0 M KOH solution. The basic mixture was extracted withEtOAc (5×300 mL), and the combined organic layers were dried overNa₂SO₄, filtered, and concentrated on a rotary evaporator to give yellowoil. The crude product 1 was used for the next step without furtherpurification. LC-MS (ESI) m/z: (M+1)⁺ 288.

Step b.

To a crude mixture of 1 (˜46.7 mmol) in MeOH (250 mL) was added KOH(25.2 g, 450 mmol). After the mixture was heated under reflux conditionfor 3 h, all volatile was removed on a rotary evaporator to give a brownsolid. The brown solid was dissolved in H₂O (200 mL) and then extractedwith EtOAc (3×200 mL). The pH of the aqueous phase was adjusted to 3-4with 10% HCl solution and extracted with EtOAc (5×200 mL). Combinedorganic layer was dried over Na₂SO₄, filtered, and concentrated on arotary evaporator to give 2 as a yellow solid (9.66 g, 80% yield). LC-MS(ESI) m/z (M+1)⁺260.

Step c.

To a mixture of 2 (1.43 g, 5.5 mmol) in DCM (50 mL) was added slowlyoxayl chloride (14.0 g, 9.5 mL, 110 mmol) followed by one drop of DMF atrt. After the resulting mixture was stirred at rt overnight (15 h), allvolatiles were removed on a rotary evaporator. The crude mixture wasused for the next step without purification.

Step d.

To a solution of 6-bromo-benzothiazole-2-carbonyl chloride 2 (˜5.5 mmol)in THF (50 mL) was added dropwise flash generated diazomethane solution(approximately 16.6 mmol of diazomethane solution generated from 25.1mmol of 4-N,N-trimethyl-benzenesulfonamide) at 0° C. The resultingmixture was stirred at 0° C. for 30 min and then the temperature wasallowed to warm to rt. After the stirring was continued at rt for 2.5 h,all volatile was removed on a rotary evaporator. The crude mixture wasused for the next step without further purification.

Step e.

To a mixture of 1-(6-bromo-benzothiazol-2-yl)-2-diazo-ethanone obtainedfrom above (˜5.5 mol) in AcOH (30 mL) was slowly added aqueous HBr (48%,0.69 mL, 6.1 mmol) at rt. The resulting mixture was stirred at rt for anadditional 2 h. All volatile was removed on a rotary evaporator to givedark solid. The crude mixture was further dried by azcotropicevaporation with toluene on a rotary evaporator (15 mL×2). Compound 3was obtained as a dark brown solid, which was used for the next stepwithout further purification.

Step f.

To a crude mixture of 2-bromo-1-(6-bromo-benzothiazol-2-yl)-ethanone A7(˜5.5 mmol) in CH₃CN (50 mL) was added pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (1.31 g, 6.1 mmol) followed by addition of DIPEA(2.14 g, 2.69 mL, 16.6 mmol) at rt. The resulting mixture was stirred atrt for 5 h, and then quenched with H₂O. The mixture was extracted withEtOAc (3×50 mL), and then the combined organic phases were washed withH₂O (50 mL) and brined (50 mL), dried over Na₂SO₄, filtered, andconcentrated on a rotary evaporator. The crude mixture was purified bycolumn chromatography eluting with hexanes/EtOAc=6:1 to 4:1 (v/v) togive the title compounds as brown solid (297 mg, 12% for total 4 stepsfrom 2). LC-MS (ESI) m/z: (M+H)⁺ 493.

Step g.

To a solution of(S)-2-(2-(6-bromobenzo[d]thiazol-2-yl)-2-oxoethyl)1-tert-butylpyrrolidine-1,2-dicarboxylate 4 (297 mg, 0.63 mmol) in xylene (5.0 mL)was added NH₄OAc (488 mg, 6.32 mmol). The resulting mixture was heatedat 145° C. for 2 h, and then all solvent was removed on a rotaryevaporator to give a crude mixture, which was subject to columnchromatography eluting with hexanes:EtOAc (1:1 to 0:1 ratio). Compound 5was obtained as brown solid (65 mg, 23%). LC-MS (ESI) m/z: (M+H)⁺ 451.

Step h.

A mixture of 5 (43 mg, 0.1 mmol), 6 (44 mg, 0.1 mmol, prepared asdescribed previously), Pd(dppf)Cl₂ (4 mg, 5 μmol), and Na₂CO₃ (35 mg,0.33 mmol) in dioxane/H₂O (2.0 mL/0.4 mL) was purged with N₂. Theresulting mixture was stirred at 90° C. for 8 h, and then diluted withH₂O. The reaction mixture was extracted with EtOAc, and combined organicwas dried over Na₂SO₄, filtered, and concentrated on a rotaryevaporator. The crude mixture was purified by column chromatographyeluting with hexanes:EtOAc=1:3 (v/v) to give 7a yellow solid (60 mg, 60%yield). LC-MS (ESI) m/z: (M+H)⁺ 683; (M−H)⁻ 681.

Step i.

To a crude solution of compound 7 (717 mg, 1.056 mmol) in THF (7.5 mL)was added HCl (4.0 M in dioxane, 10 mL) at rt. The resulting mixture wasstirred at rt for 16 h, and then all volatile was removed on a rotaryevaporator to give yellow solid. The yellow solid was washed withdiethyl ether (2×10 mL) and then further dried on a rotary evaporator togive yellow solid. The crude solid was used for the next step withoutfurther purification. The deprotected free amine from above (48 mg, —0.1mmol) was dissolved in CH₃CN (1.0 mL), was treated withN-methoxycarbonyl-L-valine (35 mg, 0.2 mmol), HATU (76 mg, 0.2 mmol) andDIEPA (52 mg, 65 μL, 0.4 mmol). The resulting mixture was stirred at rtfor 2.5 h, and then all solvents were removed on a rotary evaporator togive crude mixture. The crude mixture was purified by prep-HPLC elutingH₂O to CH₃CN, and the isolated compound was ˜80% purity. The product wasfurther purified by prep-TLC eluting with EtOAc with 5% NH₄OH to giveproduct 8 (4.5 mg) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.12 (Brs, 1H), 7.58-7.84 (m, 5H), 7.28-7.46 (m, 4H), 5.38-5.58 (m, 4H),4.36-4.42 (m, 2H), 3.87-3.98 (m, 2H), 3.71 (s, 3H), 3.69 (s, 3H),2.10-2.40 (m, 2H), 1.20-1.40 (m, 8H), 0.81-0.91 (m, 12H). LC-MS (ESI)m/z: (M+H)⁺ 795.

Biological Activity

Biological activity of the compounds of the invention was determinedusing an HCV replicon assay. The 1b_Huh-Luc/Neo-ET cell linepersistently expressing a bicistronic genotype 1b replicon in Huh 7cells was obtained from ReBLikon GMBH. This cell line was used to testcompound inhibition using luciferase enzyme activity readout as ameasurement of compound inhibition of replicon levels.

On Day 1 (the day after plating), each compound is added in triplicateto the cells. Plates incubated for 72 h prior to running the luciferaseassay. Enzyme activity was measured using a Bright-Glo Kit (cat. numberE2620) manufactured by Promega Corporation. The following equation wasused to generate a percent control value for each compound.

% Control=(Average Compound Value/Average Control)*100

The ECo value was determined using GraphPad Prism and the followingequation:

Y=Bottom+(Top−Bottom)/1+10̂((Log IC50−X)*HillSlope))

EC₅₀ values of compounds are repeated several times in the repliconassay.

Example compounds of the disclosed invention are illustrated in Tables 1and 2. Table 1 includes inhibitory activity for many of the compoundswith respect to HCV 1b. Additionally mass spectrometry results areprovided. Table 2 provides additional example compounds of theinvention. The biological activity is indicated as being *, **, ***, or****, which corresponds to EC₅₀ ranges of >1000 nM, 999 nM to 10 nM, 9.9nM to 1 nM, or <1 nM respectively.

Pharmaceutical Compositions

An eleventh aspect of the invention provides a pharmaceuticalcomposition comprising compounds of the invention. In a firstembodiment, the pharmaceutical composition further comprises one or morepharmaceutically acceptable excipients or vehicles, and optionally othertherapeutic and/or prophylactic ingredients. Such excipients are knownto those of skill in the art. The compounds of the present inventioninclude, without limitation, basic compounds such as free bases. Athorough discussion of pharmaceutically acceptable excipients and saltsis available in Remington's Pharmaceutical Sciences, 18th Edition(Easton, Pa.: Mack Publishing Company, 1990).

Depending on the intended mode of administration, the pharmaceuticalcompositions may be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, creams, ointments, lotions or the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include an effective amount of theselected drug in combination with a pharmaceutically acceptable carrierand, in addition, may include other pharmaceutical agents, adjuvants,diluents, buffers, etc.

The invention includes a pharmaceutical composition comprising acompound of the present invention including isomers, racemic ornon-racemic mixtures of isomers, or pharmaceutically acceptable salts orsolvates thereof together with one or more pharmaceutically acceptablecarriers and optionally other therapeutic and/or prophylacticingredients.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate and the like.

For oral administration, the composition will generally take the form ofa tablet, capsule, a softgel capsule nonaqueous solution, suspension orsyrup. Tablets and capsules are preferred oral administration forms.Tablets and capsules for oral use will generally include one or morecommonly used carriers such as lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. Whenliquid suspensions are used, the active agent may be combined withemulsifying and suspending agents. If desired, flavoring, coloringand/or sweetening agents may be added as well. Other optional componentsfor incorporation into an oral formulation herein include, but are notlimited to, preservatives, suspending agents, thickening agents and thelike.

A twelfth aspect of the invention provides use of the compounds of theinvention in the manufacture of a medicament.

In a first embodiment of the twelfth aspect, the medicament is for thetreatment of hepatitis C.

A thirteenth aspect of the invention provides a method of treatinghepatitis C comprising administering to a subject in need thereof, atherapeutically effective amount of a compound of the invention,optionally in a pharmaceutical composition. A pharmaceutically ortherapeutically effective amount of the composition will be delivered tothe subject. The precise effective amount will vary from subject tosubject and will depend upon the species, age, the subject's size andhealth, the nature and extent of the condition being treated,recommendations of the treating physician, and the therapeutics orcombination of therapeutics selected for administration. Thus, theeffective amount for a given situation can be determined by routineexperimentation. The subject may be administered as many doses as isrequired to reduce and/or alleviate the signs, symptoms or causes of thedisorder in question, or bring about any other desired alteration of abiological system. One of ordinary skill in the art of treating suchdiseases will be able, without undue experimentation and in relianceupon personal knowledge and the disclosure of this application, toascertain a therapeutically effective amount of the compounds of thisinvention for a given disease.

Combination Therapy

The compounds of the present invention and their isomeric forms andpharmaceutically acceptable salts thereof are useful in treating andpreventing HCV infection alone or when used in combination with othercompounds targeting viral or cellular elements or functions involved inthe HCV lifecycle. Classes of compounds useful in the invention mayinclude, without limitation, all classes of HCV antivirals. Forcombination therapies, mechanistic classes of agents that may be usefulwhen combined with the compounds of the present invention include, forexample, nucleoside and non-nucleoside inhibitors of the HCV polymerase,protease inhibitors, helicase inhibitors, NS4B inhibitors and medicinalagents that functionally inhibit the internal ribosomal entry site(IRES) and other medicaments that inhibit HCV cell attachment or virusentry, HCV RNA translation, HCV RNA transcription, replication or HCVmaturation, assembly or virus release. Specific compounds in theseclasses and useful in the invention include, but are not limited to,macrocyclic, heterocyclic and linear HCV protease inhibitors such astelaprevir (VX-950), boceprevir (SCH-503034), narlaprevir (SCH-900518),TTMN-191 (R-7227), TMC-435350 (a.k.a. TMC-435), MK-7009, BT-201335,BT-2061 (ciluprevir), BMS-650032, ACH-1625, ACH-1095 (HCV NS4A proteaseco-factor inhibitor), VX-500, VX-813, PHX-1766, PHX2054, IDX-136,IDX-316, ABT-450 EP-013420 (and congeners) and VBY-376; the NucleosidicHCV polymerase (replicase) inhibitors useful in the invention include,but are not limited to, R7128, PSI-7851, IDX-184, IDX-102, R1479,UNX-08189, PSI-6130, PSI-938 and PSI-879 and various other nucleosideand nucleotide analogs and HCV inhibitors including (but not limited to)those derived as 2′-C-methyl modified nucleos(t)ides, 4′-aza modifiednucleos(t)ides, and 7′-deaza modified nucleos(t)ides. Non-nuclosidic HCVpolymerase (replicase) inhibitors useful in the invention, include, butare not limited to , HCV-796, HCV-371, VCH-759, VCH-916, VCH-222,ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190,A-837093, JKT-109, GL-59728 and GL-60667.

In addition, NS5A inhibitors of the present invention may be used incombination with cyclophyllin and immunophyllin antagonists (eg, withoutlimitation, DEBIO compounds, NM-811 as well as cyclosporine and itsderivatives), kinase inhibitors, inhibitors of heat shock proteins(e.g., HSP90 and HSP70), other immunomodulatory agents that may include,without limitation, interferons (-alpha, -beta, -omega, -gamma, -lambdaor synthetic) such as Intron A™, Roferon-A™, Canferon-A300™, Advaferon™,Infergen™, Humoferon™, Sumiferon MP™, Alfafcronc™, IFN-β™, Fcron™ andthe like; polyethylene glycol derivatized (pegylated) interferoncompounds, such as PEG interferon-α-2a (Pegasys™), PEG interferon-α-2b(PEGIntron™), pegylated IFN-α-con1 and the like; long actingformulations and derivatizations of interferon compounds such as thealbumin-fused interferon, Albuferon™, Locteron™ and the like;interferons with various types of controlled delivery systems (e.g.ITCA-638, omega-interferon delivered by the DUROS™ subcutaneous deliverysystem); compounds that stimulate the synthesis of interferon in cells,such as resiquimod and the like; interleukins; compounds that enhancethe development of type 1 helper T cell response, such as SCV-07 and thelike; TOLL-like receptor agonists such as CpG-10101 (actilon),isotorabine, ANA773 and the like; thymosin α−1; ANA-245 and ANA-246;histamine dihydrochloride; propagermanium; tetrachlorodecaoxide;ampligen; IMP-321; KRN-7000; antibodies, such as civacir, XTL-6865 andthe like and prophylactic and therapeutic vaccines such as InnoVa C, HCVE1E2/MF59 and the like. In addition, any of the above-described methodsinvolving administering an NS5A inhibitor, a Type T interferon receptoragonist (e.g., an IFN-α) and a Type IT interferon receptor agonist(e.g., an IFN-γ) can be augmented by administration of an effectiveamount of a TNF-α antagonist. Exemplary, non-limiting TNF-α antagoniststhat are suitable for use in such combination therapies include ENBREL™,REMICADE™ and HUMIRA™.

In addition, NS5A inhibitors of the present invention may be used incombination with antiprotozoans and other antivirals thought to beeffective in the treatment of HCV infection, such as, withoutlimitation, the prodrug nitazoxanide. Nitazoxanide can be used as anagent in combination the compounds disclosed in this invention as wellas in combination with other agents useful in treating HCV infectionsuch as peginterferon alfa-2a and ribavarin (see, for example,Rossignol, J F and Keeffe, E B, Future Microbiol. 3:539-545, 2008).

NS5A inhibitors of the present invention may also be used withalternative forms of interferons and pegylated interferons, ribavirin orits analogs (e.g., tarabavarin, levoviron), microRNA, small interferingRNA compounds (e.g., SIRPLEX-140-N and the like), nucleotide ornucleoside analogs, immunoglobulins, hepatoprotectants,anti-inflammatory agents and other inhibitors of NS5A. Inhibitors ofother targets in the HCV lifecycle include NS3 helicase inhibitors; NS4Aco-factor inhibitors; antisense oligonucleotide inhibitors, such asISIS-14803, AVI-4065 and the like; vector-encoded short hairpin RNA(shRNA); HCV specific ribozymes such as heptazyme, RPI, 13919 and thelike; entry inhibitors such as HepeX-C, HuMax-HepC and the like; alphaglucosidase inhibitors such as celgosivir, UT-231B and the like;KPE-02003002 and BIVN 401 and IMPDH inhibitors. Other illustrative HCVinhibitor compounds include those disclosed in the followingpublications: U.S. Pat. No. 5,807,876; U.S. Pat. No. 6,498,178; U.S.Pat. No. 6,344,465; U.S. Pat. No. 6,054,472; WO97/40028; WO98/40381;WO00/56331, WO 02/04425; WO 03/007945; WO 03/010141; WO 03/000254; WO01/32153; WO 00/06529; WO 00/18231; WO 00/10573; WO 00/13708; WO01/85172; WO 03/037893; WO 03/037894; WO 03/037895; WO 02/100851; WO02/100846; EP 1256628; WO 99/01582; WO 00/09543; WO02/18369; WO98/17679,WO00/056331; WO 98/22496; WO 99/07734; WO 05/073216, WO 05/073195 and WO08/021,927.

Additionally, combinations of, for example, ribavirin and interferon,may be administered as multiple combination therapy with at least one ofthe compounds of the present invention. The present invention is notlimited to the aforementioned classes or compounds and contemplatesknown and new compounds and combinations of biologically active agents(see, Strader, D. B., Wright, T., Thomas, D. L. and Seeff, L. B., AASLDPractice Guidelines. 1-22, 2009 and Manns, M. P., Foster, G. R.,Rockstroh, J. K., Zeuzem, S., Zoulim, F. and Houghton, M., NatureReviews Drug Discovery. 6:991-1000, 2007, Pawlotsky, J-M., Chevaliez, S,and McHutchinson, J. G., Gastroenterology. 132:179-1998, 2007,Lindenbach, B. D. and Rice, C. M., Nature 436:933-938, 2005, Klebl, B.M., Kurtenbach, A., Salassidis, K., Daub, H. and Herget, T., AntiviralChemistry & Chemotherapy. 16:69-90, 2005, Beaulieu, P. L., CurrentOpinion in Investigational Drugs. 8:614-634, 2007. Kim, S-J., Kim, J-H.,Kim, Y-G., Lim, H-S, and Oh, W-J., The Journal of Biological Chemistry.48:50031-50041, 2004, Okamoto, T., Nishimura, Y., Ichimura, T., Suzuki,K., Miyamura, T., Suzuki, T., Moriishi, K. and Matsuura, Y., The EMBOJournal. Jan. 11, 2006, Soriano, V., Peters, M. G. and Zeuzem, S.Clinical Infectious Diseases. 48:313-320, 2009, Huang, Z., Murray, M. G.and Secrist, J. A., Antiviral Research. 71:351-362, 2006 and Neyts, J.,Antiviral Research. 71:363-371, 2006, each of which is incorporated byreference in their entirety herein). It is intended that combinationtherapies of the present invention include any chemically compatiblecombination of a compound of this inventive group with other compoundsof the inventive group or other compounds outside of the inventivegroup, as long as the combination does not eliminate the anti-viralactivity of the compound of this inventive group or the anti-viralactivity of the pharmaceutical composition itself.

Combination therapy can be sequential, that is treatment with one agentfirst and then a second agent (for example, where each treatmentcomprises a different compound of the invention or where one treatmentcomprises a compound of the invention and the other comprises one ormore biologically active agents) or it can be treatment with both agentsat the same time (concurrently). Sequential therapy can include areasonable time after the completion of the first therapy beforebeginning the second therapy. Treatment with both agents at the sametime can be in the same daily dose or in separate doses. Combinationtherapy need not be limited to two agents and may include three or moreagents. The dosages for both concurrent and sequential combinationtherapy will depend on absorption, distribution, metabolism andexcretion rates of the components of the combination therapy as well asother factors known to one of skill in the art. Dosage values will alsovary with the severity of the condition to be alleviated. It is to befurther understood that for any particular subject, specific dosageregimens and schedules may be adjusted over time according to theindividual's need and the professional judgment of the personadministering or supervising the administration of the combinationtherapy.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to one of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the invention as defined in the appended claims.

TABLE 1 Inhibition of HCV MS Compound Structure genotype 1b (M + H)+ 1

**** 789.4 2

**** 789.4 3

**** 821.4 4

**** 793.4 5

**** 793.4 6

**** 793.4 7

**** 823.4 8

**** 823.4 9

**** 819.4 10

**** 819.4 11

**** 791.4 12

*** 791.4 13

**** 790.4 14s

**** 822.4 15

**** 878.4 16

**** 878.4 17

**** 791.4 18

**** 822.4 19

**** 790.4 20

**** 789.4 21

**** 790.4 22

**** 790.4 23

**** 864.4 24

**** 848.4 25

**** 864.4 26

**** 824.4 27

**** 836.4 28

**** 836.4 29

**** 848.4 30

**** 866.4 31

**** 823.4 32

**** 824.4 33

**** 837.4 34

**** 849.4 35

**** 866.4 36

**** 823.4 37

**** 837.4 38

**** 849.4 39

**** 832.4 40

**** 806.4 41

**** 762.4 42

**** 832.4 43

**** 806.4 44

**** 762.4 45

**** 824.4 46

**** 831.4 47

**** 831.4 48

**** 824.4 49

**** 832.4 50

**** 832.4 51

**** 832.4 52

**** 832.4 53

**** 791.4 54

**** 859.4 55

**** 877.4 56

**** 824.4 57

**** 808.4 58

**** 842.4 59

**** 850.4 60

**** 825.4 61

**** 833.4 62

**** 833.4 63

**** 824.4 64

**** 841.4 65

**** 849.4 66

**** 807.4 67

**** 841.4 68

**** 849.4 69

**** 837.4 70

**** 867.4 71

**** 866.4 72

**** 908.4 73

**** 874.4 74

**** 791.4 75

**** 875.5 76

**** 806.4 77

** 874.4 78

**** 888.4 79

**** 820.4 80

**** 859.4 81

**** 895.4 82

**** 867.4 83

**** 790.4 84

**** 832.4 85

**** 803.4 86

**** 845.4 87

**** 837.4 88

**** 894.4 89

**** 936.4 90

**** 866.4 91

**** 908.4 92

**** 936.4 93

**** 791.4 94

**** 825.4 95

**** 833.4 96

**** 808.4 97

**** 876.4 98

**** 892.4 99

**** 865.4 100

**** 866.4 101

**** 866.4 102

**** 790.4 103

**** 824.4 104

**** 845.4 105

**** 865.4 106

**** 883.4 107

**** 842.4 108

**** 892.4 109

**** 876.4 110

**** 871.4 111

**** 883.4 112

**** 935.4 113

**** 935.4 114

**** 883.4 115

**** 839.4 116

**** 835.4 117

**** 936.4 118

**** 908.4 119

**** 842.4 120

**** 850.4 121

**** 912.4 122

**** 884.4 123

**** 850.4 124

**** 842.4 125

**** 912.4 126

**** 808.4 127

**** 884.4 128

**** 850.4 129

**** 884.4 130

**** 789.4 131

**** 839.4 132

**** 839.4 133

**** 873.4 134

**** 884.4 135

**** 926.4 136

**** 926.4 137

**** 839.4 138

**** 839.4 139

**** 805.4 140

**** 805.4 141

**** 891.4 142

**** 817.4 143

**** 785.4 144

**** 865.4 145

**** 891.4 146

**** 806.4 147

**** 848.4 148

**** 840.4 149

**** 910.4 150

**** 808.4 151

**** 850.4 152

**** 842.4 153

**** 912.4 154

**** 954.4 155

**** 842.4 156

**** 912.4 157

816.4 158

858.4 159

806.4 160

848.4 161

804.4 162

846.4 163

886.4 164

878.4 165

884.4 166

850.4 167

842.4 168

855.4 169

881.4 170

821.4 171

845.4 172

841.4 173

761.4 174

**** 763.4 175

**** 767.3 176

**** 795.4 177

**** 767.4 178

**** 793.4 179

**** 797.4 180

**** 793.4 181

**** 797.4 182

**** 767.4 183

**** 852.4 184

**** 797.4 185

**** 852.4 186

**** 796.4 187

**** 764.4 188

*** 798.4 189

**** 805.4 190

**** 805.4 191

**** 806.4 192

**** 806.4 193

**** 764.4 194

**** 806.4 195

**** 798.4 196

**** 798.4 197

**** 798.4 198

**** 764.4 199

**** 798.4 200

**** 798.4 201

**** 806.4 202

**** 806.4 203

**** 847.4 204

**** 764.4 205

**** 848.4 206

*** 848.4 207

**** 763.4 208

**** 797.4 209

**** 764.4 210

**** 798.4 211

**** 806.4 212

**** 839.4 213

**** 809.4 214

** 763.4 215

**** 805.4 216

**** 806.4 217

*** 848.4 218

**** 815.4 219

806.4 220

779.4 221

821.4 222

779.4 223

821.4 224

795.4 225

791.4 226

735.4 227

819.4 228

759.4 229

**** 796.4 230

**** 864.3 231

**** 793.4 232

**** 793.4 233

**** 861.4 234

**** 780.4 235

**** 848.3 236

**** 780.4 237

**** 848.3 238

**** 812.4 239

**** 776.3 240

**** 796.4 241

**** 830.3 242

**** 872.4 243

**** 824.4 244

**** 843.4 245

**** 829.4 246

**** 773.3 247

**** 856.4 248

**** 892.4 249

**** 814.4 250

** 716.3 251

**** 813.4 252

**** 827.4 253

**** 796.4 254

**** 856.4 255

**** 814.4 256

**** 813.4 257

**** 827.4 258

**** 796.4 259

**** 822.4 260

**** 814.4 261

*** 821.5 262

**** 822.5 263

**** 890.4 264

*** 830.5 265

**** 818.4 266

**** 766.4 267

* 508.3 268

** 708.4 269

**** 830.4 270

**** 898.4 271

**** 826.4 272

**** 774.3 273

*** 741.4 274

*** 793.4 275

**** 797.4 276

**** 813.4 277

**** 813.4 278

**** 757.3 279

**** 897.4 280

**** 814.4 281

**** 814.4 282

**** 855.4 283

**** 847.4 284

899.4 286

**** 864.4 287

**** 806.4 288

**** 874.4 289

**** 876.4 290

**** 794.4 291

**** 898.5 292

**** 816.4 293

**** 858.4 294

**** 850.4 295

**** 920.4 296

**** 814.4 297

**** 856.4 298

**** 848.4 299

**** 918.4

TABLE 2 Compound Structure 300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

What is claimed is:
 1. A compound having formula IIIe:

or a pharmaceutically acceptable salt thereof, wherein: X, X′, X^(b),and X^(c) are each —CH₂—; each R^(a) is hydrogen; each r is 3; Z and Z′are each independently —U—(CR⁴ ₂)_(t)—NR⁵—U—O—R⁸, wherein, each U isindependently selected from the group consisting of —C(O)—, —C(S)— and—S(O)₂—, each R⁴ and R⁵ is independently selected from the groupconsisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl, R⁸ is hydrogen orC₁ to C₈ alkyl, and t is independently 0, 1, 2, 3, or
 4. 2. The compoundof claim 1, wherein Z and Z′ are the same.
 3. The compound of claim 1,wherein each U is —C(O)—.
 4. The compound of claim 1, wherein the twoR⁴s are different.
 5. The compound of claim 4, wherein one R⁴ ishydrogen and another R⁴ is C₁ to C₈ alkyl.
 6. The compound of claim 4,wherein one R⁴ is hydrogen and another R⁴ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, andtert-butyl.
 7. The compound of claim 4, wherein one R⁴ is hydrogen andanother R⁴ is isopropyl.
 8. The compound of claim 1, wherein R⁵ ishydrogen.
 9. The compound of claim 1, wherein R⁸ is C₁ to C₈ alkyl. 10.The compound of claim 1, wherein R⁸ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, andtert-butyl.
 11. The compound of claim 1, wherein R⁸ is methyl.
 12. Acompound of the formula


13. A pharmaceutical composition comprising a compound of formula IIIeand one or more pharmaceutically acceptable excipients or vehicles,wherein the compound of formula IIIe has the structure:

or a pharmaceutically acceptable salt thereof, wherein: X, X′, X^(b),and X^(c) are each —CH₂—; each R^(a) is hydrogen; each r is 3; Z and Z′are each independently —U—(CR⁴ ₂)_(t)—NR⁵—U—O—R⁸, wherein, each U isindependently selected from the group consisting of —C(O)—, —C(S)— and—S(O)₂—, each R⁴ and R⁵ is independently selected from the groupconsisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl, R⁸ is hydrogen orC₁ to C₈ alkyl, and t is independently 0, 1, 2, 3, or
 4. 14. Thepharmaceutical composition of claim 13, wherein Z and Z′ are the same.15. The pharmaceutical composition of claim 13, wherein each U is—C(O)—.
 16. The pharmaceutical composition of claim 13, wherein the twoR⁴s are different.
 17. The pharmaceutical composition of claim 13,wherein one R⁴ is hydrogen and another R⁴ is isopropyl.
 18. Thepharmaceutical composition of claim 13, wherein R⁵ is hydrogen.
 19. Thepharmaceutical composition of claim 13, wherein R⁸ is methyl.
 20. Thepharmaceutical composition of claim 13, wherein the compound of formulaIIIe is: